Cyclic protein tyrosine kinase inhibitors

ABSTRACT

Novel cyclic compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders.

RELATED APPLICATIONS

This application is a continuation of Ser. No. 15/163,750 filed May 25,2016, now allowed, which is a continuation of Ser. No. 14/620,244, filedFeb. 12, 2015, now U.S. Pat. No. 9,382,219, which is a continuation ofSer. No. 14/226,868, filed Mar. 27, 2014, now U.S. Pat. No. 8,993,567,which is a continuation of Ser. No. 11/271,626, filed Nov. 10, 2005, nowU.S. Pat. No. 8,716,323, which is a continuation of application Ser. No.10/378,373 filed Mar. 3, 2003, which is a continuation of applicationSer. No. 09/548,929 filed Apr. 13, 2000, now U.S. Pat. No. 6,596,746,which claims priority from provisional application No. 60/129,510 filedApr. 15, 1999. The entire disclosure of each of the foregoingapplications is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to cyclic compounds and salts thereof, tomethods of using such compounds in treating protein tyrosinekinase-associated disorders such as immunologic and oncologic disorders,and to pharmaceutical compositions containing such compounds.

BACKGROUND OF THE INVENTION

Protein tyrosine kinases (PTKs) are enzymes which, in conjuction withATP as a substrate, phosphorylate tyrosine residues in peptides andproteins. These enzymes are key elements in the regulation of cellsignaling including cell proliferation and cell differentiation. PTKscomprise, inter alia, receptor tyrosine kinases (RPTKs), includingmembers of the epidermal growth factor kinase family (e.g., HER1 andHER2), platelet derived growth factor (PDGF), and kinases that play arole in angiogenesis (Tie-2 and KDR); and, in addition, non-receptortyrosine kinases, including members of the Syk, JAK and Src (e.g. Src,Fyn, Lyn, Lck and Blk) families (see Bolen, J. B., Rowley, R. B., Spana,C., and Tsygankov, A. Y., “The src family of tyrosine protein kinases inhemopoietic signal transduction”, FASEB J., 6, 3403-3409 (1992);Ullrich, A. and Schlessinger, J., “Signal transduction by receptors withtyrosine kinase activity”, Cell, 61, 203-212 (1990); and Ihle, J. N.,“The Janus protein tyrosine kinases in hematopoetic cytokine signaling”,Sem. Immunol., 7, 247-254 (1995)).

Enhanced activity of PTKs has been implicated in a variety of malignantand nonmalignant proliferative diseases. In addition, PTKs play acentral role in the regulation of cells of the immune system. PTKinhibitors can thus impact a wide variety of oncologic and immunologicdisorders. Such disorders may be ameliorated by selective inhibition ofa certain receptor or non-receptor PTK, such as Lck, or due to thehomology among PTK classes, by inhibition of more than one PTK by aninhibitor.

A PTK of particular interest is Lck which is found in T cells where itis involved in phosphorylating key protein substrates. It is requiredfor productive antigen receptor signaling and cell activation. In theabsence of Lck activity, the T cell receptor (TCR) zeta chain is notphosphorylated, the kinase ZAP-70 is not activated, and Ca²⁺mobilization essential for T cell activation does not occur (see Weiss,A. and Littman, D. R., “Signal transduction by lymphocyte antigenreceptors”, Cell, 76, 263-274 (1994); Iwashima, M., Irving, B. A., vanOers, N. S. C., Chan, A. C., and Weiss, A., “Sequential interactions ofthe TCR with two distinct cytoplasmic tyrosine kinases”, Science, 263,1136-1139 (1994); and Chan, A. C., Dalton, M., Johnson, R., Kong, G.,Wang, T., Thoma, R., and Kurosaki, T., “Activation of ZAP-70 kinaseactivity by phosphorylation of tyrosine 493 is required for lymphocyteantigen receptor function”, EMBO J., 14, 2499-2508 (1995)). Inhibitorsof Lck are thus useful in the treatment of T-cell mediated disorderssuch as chronic diseases with an important T cell component, for examplerheumatoid arthritis, multiple sclerosis and lupus, as well as acutediseases where T cells are known to play an essential role, for exampleacute transplant rejection and delayed-type hypersensitivity (DTH)reactions.

SUMMARY OF THE INVENTION

The present invention provides cyclic compounds of the following formulaI and salts thereof, for use as protein tyrosine kinase inhibitors:

where

Q is:

-   -   (1) a 5-membered heteroaryl ring;    -   (2) a 6-membered heteroaryl ring; or    -   (3) an aryl ring;    -   optionally substituted with one or more groups R₁;

Z is:

-   -   (1) a single bond;    -   (2) —R₁₅C═CH—; or    -   (3) —(CH₂)_(m)—, where m is 1 to 2;        X₁ and X₂ are each hydrogen, or together form ═O or ═S;

R₁ is:

-   -   (1) hydrogen or R₆,        -   where R₆ is alkyl, alkenyl, alkynyl, cycloalkyl,            cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl,            aralkyl, heterocyclo, or heterocycloalkyl, each of which is            unsubstituted or substituted with Z₁, Z₂ and one or more            (preferably, one or two) groups Z₃;    -   (2) —OH or —OR₆;    -   (3) —SH or —SR₆;    -   (4) —C(O)₂H, —C(O)_(q)R₆, or —O—C(O)_(q)R₆, where q is 1 or 2;    -   (5) —SO₃H or —S(O)_(q)R₆;    -   (6) halo;    -   (7) cyano;    -   (8) nitro;    -   (9) —Z₄—NR₇R₈;    -   (10) —Z₄—N(R₉)—Z₅—NR₁₀R₁₁;    -   (11) —Z₄—N(R₁₂)—Z₅—R₆;    -   (12) —P(O)(OR₆)₂;        R₂ and R₃ are each independently:    -   (1) hydrogen or R₆;    -   (2) —Z₄—R₆; or    -   (3) —Z₁₃—NR₇R₈;        R₄ and R₅:    -   (1) are each independently hydrogen or R₆;    -   (2) —Z₄—N(R₉)—Z₅—NR₁₀R₁₁;    -   (3) —N(R₉)Z₄R₆; or    -   (4) together with the nitrogen atom to which they are attached        complete a 3- to 8-membered saturated or unsaturated        heterocyclic ring which is unsubstituted or substituted with Z₁,        Z₂ and Z₃, which heterocyclic ring may optionally have fused to        it a benzene ring itself unsubstituted or substituted with Z₁,        Z₂ and Z₃;        R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂:    -   (1) are each independently hydrogen or R₆;    -   (2) R₇ and R₈ may together be alkylene, alkenylene or        heteroalkyl, completing a 3- to 8-membered saturated or        unsaturated ring with the nitrogen atom to which they are        attached, which ring is unsubstituted or substituted with Z₁, Z₂        and Z₃; or    -   (3) any two of R₉, R₁₀ and R₁₁ may together be alkylene or        alkenylene completing a 3- to 8-membered saturated or        unsaturated ring together with the nitrogen atoms to which they        are attached, which ring is unsubstituted or substituted with        Z₁, Z₂ and Z₃;

R₁₃ is:

-   -   (1) cyano;    -   (2) nitro;    -   (3) —NH₂;    -   (4) —NHOalkyl;    -   (5) —OH;    -   (6) —NHOaryl;    -   (7) —NHCOOalkyl;    -   (8) —NHCOOaryl;    -   (9) —NHSO₂alkyl;    -   (10) —NHSO₂aryl;    -   (11) aryl;    -   (12) heteroaryl;    -   (13) —Oalkyl; or    -   (14) —Oaryl;

R₁₄ is:

-   -   (1) —NO₂;    -   (2) —COOalkyl; or    -   (3) —COOaryl;

R₁₅ is:

-   -   (1) hydrogen;    -   (2) alkyl;    -   (3) aryl;    -   (4) arylalkyl; or    -   (5) cycloalkyl;        Z₁, Z₂ and Z₃ are each independently:    -   (1) hydrogen or Z₆, where Z₆ is (i) alkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,        aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or        heterocycloalkyl; (ii) a group (i) which is itself substituted        by one or more of the same or different groups (i); or (iii) a        group (i) or (ii) which is substituted by one or more of the        following groups (2) to (16) of the definition of Z₁, Z₂ and Z₃;    -   (2) —OH or —OZ₆;    -   (3) —SH or —SZ₆;    -   (4) —C(O)_(q)H, —C(O)_(q)Z₆, or —O—C(O)_(q)Z₆;    -   (5) —SO₃H, —S(O)_(q)Z₆; or S(O)_(q)N(Z₉)Z₆;    -   (6) halo;    -   (7) cyano;    -   (8) nitro;    -   (9) —Z₄—NZ₇Z₈;    -   (10) —Z₄—N(Z₉)—Z₅—NZ₇Z₈;    -   (11) —Z₄—N(Z₁₀)—Z₅—Z₆;    -   (12) —Z₄—N(Z₁₀)—Z₅—H;    -   (13) oxo;    -   (14) —O—C(O)—Z₆;    -   (15) any two of Z₁, Z₂, and Z₃ may together be alkylene or        alkenylene completing a 3- to 8-membered saturated or        unsaturated ring together with the atoms to which they are        attached; or    -   (16) any two of Z₁, Z₂, and Z₃ may together be —O—(CH₂)_(r)—O—,        where r is 1 to 5, completing a 4- to 8-membered saturated or        unsaturated ring together with the atoms to which they are        attached;        Z₄ and Z₅ are each independently:    -   (1) a single bond;    -   (2) —Z₁₁—S(O)_(q)—Z₁₂—;    -   (3) —Z₁₁—C(O)—Z₁₂—;    -   (4) —Z₁₁—C(S)—Z₁₂—;    -   (5) —Z₁₁—O—Z₁₂—;    -   (6) —Z₁₁—S—Z₁₂—;    -   (7) —Z₁₁—O—C(O)—Z₁₂—; or    -   (8) —Z₁₁—C(O)—O—Z₁₂—;        Z₇, Z₈, Z₉ and Z₁₀:    -   (1) are each independently hydrogen or Z₆;    -   (2) Z₇ and Z₈, or Z₆ and Z₁₀, may together be alkylene or        alkenylene, completing a 3- to 8-membered saturated or        unsaturated ring together with the atoms to which they are        attached, which ring is unsubstituted or substituted with Z₁, Z₂        and Z₃; or    -   (3) Z₇ or Z₈, together with Z₉, may be alkylene or alkenylene        completing a 3- to 8-membered saturated or unsaturated ring        together with the nitrogen atoms to which they are attached,        which ring is unsubstituted or substituted with Z₁, Z₂ and Z₃;        Z₁₁ and Z₁₂ are each independently:    -   (1) a single bond;    -   (2) alkylene;    -   (3) alkenylene; or    -   (4) alkynylene; and

Z₁₃ is:

-   -   (1) a single bond;    -   (2) —Z₁₁—S(O)_(q)—Z₁₂—;    -   (3) —Z₁₁—C(O)—Z₁₂—;    -   (4) —Z₁₁—C(S)—Z₁₂—;    -   (5) —Z₁₁—O—Z₁₂—;    -   (6) —Z₁₁—S—Z₁₂—;    -   (7) —Z₁₁—O—C(O)—Z₁₂—;    -   (8) —Z₁₁—C(O)—O—Z₁₂—;    -   (9) —C(NR₁₃)—;    -   (10) —C(CHR₁₄)—; or    -   (11) —C(C(R₁₄)₂)—.

Compounds within formula I include compounds of the following formula IIand salts thereof:

where

n is 1 or 2A is selected from carbon and nitrogen;B is selected from nitrogen, oxygen and sulfur;X₃ is oxygen or sulfur; andR₁, R₂, R₃, R₄ and R₅ are as described above.

DETAILED DESCRIPTION OF THE INVENTION

The following are definitions of terms used in this specification. Theinitial definition provided for a group or term herein applies to thatgroup or term throughout the present specification, individually or aspart of another group, unless otherwise indicated.

The terms “alk” or “alkyl” refer to straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbonatoms. The expression “lower alkyl” refers to alkyl groups of 1 to 4carbon atoms.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups of 2 to 10, preferably 2 to 4, carbon atoms having at least onedouble bond. Where an alkenyl group is bonded to a nitrogen atom, it ispreferred that such group not be bonded directly through a carbonbearing a double bond.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups of 2 to 10, preferably 2 to 4, carbon atoms having at least onetriple bond. Where an alkynyl group is bonded to a nitrogen atom, it ispreferred that such group not be bonded directly through a carbonbearing a triple bond.

The term “alkylene” refers to a straight chain bridge of 1 to 5 carbonatoms connected by single bonds (e.g., —(CH₂)_(x)— wherein x is 1 to 5),which may be substituted with 1 to 3 lower alkyl groups.

The term “alkenylene” refers to a straight chain bridge of 2 to 5 carbonatoms having one or two double bonds that is connected by single bondsand may be substituted with 1 to 3 lower alkyl groups. Exemplaryalkenylene groups are —CH═CH—CH═CH—, —CH₂—CH═CH—, —CH₂—CH═CH—CH₂—,—C(CH₃)₂CH═CH— and —CH(C₂H₅)—CH═CH—.

The term “alkynylene” refers to a straight chain bridge of 2 to 5 carbonatoms that has a triple bond therein, is connected by single bonds, andmay be substituted with 1 to 3 lower alkyl groups. Exemplary alkynylenegroups are —C≡C—, —CH₂—C≡C—, —CH(CH₃)—C≡C— and —C≡C—CH(C₂H₅)CH₂—.

The terms “ar” or “aryl” refer to aromatic cyclic groups (for example 6membered monocyclic, 10 membered bicyclic or 14 membered tricyclic ringsystems) which contain 6 to 14 carbon atoms. Exemplary aryl groupsinclude phenyl, naphthyl, biphenyl and anthracene.

The terms “cycloalkyl” and “cycloalkenyl” refer to cyclic hydrocarbongroups of 3 to 12 carbon atoms.

The terms “halogen” and “halo” refer to fluorine, chlorine, bromine andiodine.

The term “unsaturated ring” includes partially unsaturated and aromaticrings.

The terms “heterocycle”, “heterocyclic” or “heterocyclo” refer to fullysaturated or unsaturated, including aromatic (i.e. “heteroaryl”) cyclicgroups, for example, 4 to 7 membered monocyclic, 7 to 11 memberedbicyclic, or 10 to 15 membered tricyclic ring systems, which have atleast one heteroatom in at least one carbon atom-containing ring. Eachring of the heterocyclic group containing a heteroatom may have 1, 2, 3or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/orsulfur atoms, where the nitrogen and sulfur heteroatoms may optionallybe oxidized and the nitrogen heteroatoms may optionally be quaternized.The heterocyclic group may be attached at any heteroatom or carbon atomof the ring or ring system.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl,benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl,tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (suchas furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The term “heteroaryl” refers to aromatic heterocyclic groups.

Exemplary heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl,thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazolyl, triazinyl, and the like.

Where q is 1 or 2, “—C(O)_(q)H” denotes —C(O)—H or —C(O)—OH;“—C(O)_(q)R₆” or “—C(O)_(q)Z₆” denote, respectively, —C(O)—R₆ or—C(O)—OR₆, or —C(O)—Z₆ or —C(O)—OZ₆; “—O—C(O)_(q)R₆” or “—O—C(O)_(q)Z₆”denote, respectively, —O—C(O)—R₆ or —O—C(O)—OR₆, or —O—C(O)—Z₆ or—O—C(O)—OZ₆; and “—S(O)_(q)R₆” or “—S(O)_(q)Z₆” denote, respectively,—SO—R₆ or —SO₂—R₆, or —SO—Z₆ or —SO₂—Z₆.

Compounds of the formula I may in some cases form salts which are alsowithin the scope of this invention. Reference to a compound of theformula I herein is understood to include reference to salts thereof,unless otherwise indicated. The term “salt(s)”, as employed herein,denotes acidic and/or basic salts formed with inorganic and/or organicacids and bases. Zwitterions (internal or inner salts) are includedwithin the term “salt(s)” as used herein (and may be formed, forexample, where the R substituents comprise an acid moiety such as acarboxyl group). Also included herein are quaternary ammonium salts suchas alkylammonium salts. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, although other saltsare useful, for example, in isolation or purification steps which may beemployed during preparation. Salts of the compounds of the formula I maybe formed, for example, by reacting a compound I with an amount of acidor base, such as an equivalent amount, in a medium such as one in whichthe salt precipitates or in an aqueous medium followed bylyophilization.

Exemplary acid addition salts include acetates (such as those formedwith acetic acid or trihaloacetic acid, for example, trifluoroaceticacid), adipates, alginates, ascorbates, aspartates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates,hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates,lactates, maleates, methanesulfonates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates (such as those formed with sulfuricacid), sulfonates (such as those mentioned herein), tartrates,thiocyanates, toluenesulfonates, undecanoates, and the like.

Exemplary basic salts (formed, for example, where the R substituentscomprise an acidic moiety such as a carboxyl group) include ammoniumsalts, alkali metal salts such as sodium, lithium, and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases (for example, organic amines) such as benzathines,dicyclohexylamines, hydrabamines, N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like. The basic nitrogen-containing groupsmay be quaternized with agents such as lower alkyl halides (e.g. methyl,ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), longchain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound of theformula I, or a salt and/or solvate thereof. Solvates of the compoundsof formula I are preferably hydrates.

All stereoisomers of the present compounds, such as those which mayexist due to asymmetric carbons on the R substituents of the compound ofthe formula I, including enantiomeric and diastereomeric forms, arecontemplated within the scope of this invention. Individualstereoisomers of the compounds of the invention may, for example, besubstantially free of other isomers, or may be admixed, for example, asracemates or with all other, or other selected, stereoisomers. Thechiral centers of the present invention can have the S or Rconfiguration as defined by the IUPAC 1974 Recommendations.

Throughout the specification, groups and substituents thereof are chosento provide stable moieties and compounds.

Preferred Compounds

Preferred compounds of the present invention are compounds of theformula I, and salts thereof, wherein Q is thiazole and wherein one ormore, and especially all, of Z, X₁, X₂ R₁, R₂, R₃, R₄, and R₅ areselected from the following definitions:

Z is a single bond;

R₁ is selected from hydrogen, halo, alkyl, aryl, alkoxy, alkoxycarbonyl,or aryloxycarbonyl and is more preferably hydrogen;

X₁ and X₂ together form ═O or ═S and more preferably form ═O;

R₂ is hydrogen;

R₃ is selected from —Z₄—R₆ or —Z₁₃—NR₇R₈ and is more preferably —Z₄—R₆wherein Z₄ is a single bond and R₆ is aryl or heteroaryl which isunsubstituted or substituted with Z₁, Z₂ and one or more (preferably,one or two) groups Z₃;

R₄ is hydrogen; and

R₅ is selected from aryl groups or heteroaryl groups which aresubstituted with Z₁, Z₂ and one or more (such as one or two) groups Z₃.

Methods of Preparation

The compounds of the formula I may be prepared by methods such as thoseillustrated in the following Schemes A through E and I through XI.Solvents, temperatures, pressures, and other reaction conditions mayreadily be selected by one of ordinary skill in the art. All documentscited are incorporated herein by reference in their entirety. Startingmaterials are commercially available or readily prepared by one ofordinary skill in the art. Constituents of compounds are as definedelsewhere in the specification or as specifically defined in a scheme.

The methods described herein may be carried out with starting materialsand/or reagents in solution or alternatively, where appropriate, withone or more starting materials or reagents bound to a solid support (see(1) Thompson, L. A., Ellman, J. A., Chemical Reviews, 96, 555-600(1996); (2) Terrett, N. K., Gardner, M., Gordon, D. W., Kobylecki, R.J., Steele, J., Tetrahedron, 51, 8135-8173 (1995); (3) Gallop, M. A.,Barrett, R. W., Dower, W. J., Fodor, S. P. A., Gordon, E. M., Journal ofMedicinal Chemistry, 37, 1233-1251 (1994); (4) Gordon, E. M., Barrett,R. W., Dower, W. J., Fodor, S. P. A., Gallop, M. A., Journal ofMedicinal Chemistry, 37, 1385-1401 (1994); (5) Balkenhohl, F., von demBussche-Hünnefeld, Lansky, A., Zechel, C., Angewandte ChemieInternational Edition in English, 35, 2288-2337 (1996); (6) Balkenhohl,F., von dem Bussche-Hünnefeld, Lansky, A., Zechel, C., AngewandteChemie, 108, 2436-2487 (1996); and (7) Sofia, M. J., Drugs DiscoveryToday, 1, 27-34 (1996)).

Scheme A illustrates a general method for forming compound Ia, which isa compound of the formula I where X₁ and X₂ together form ═O. As shownin Scheme A, compound Ia where R₂ and R₃ are hydrogen may be formed bysaponification of i, (R* is a carboxyl protecting group such as alkyl orarylalkyl) followed by reaction with amine iii by methods known in theart. Alternatively i may be reacted with R₂L, where L is a leaving groupsuch as halogen (for example, in equimolar portions), optionallyfollowed by reaction with R₃L (for example, in equimolar portions) toform ii. Also alternatively, i may be subjected to reductive aminationusing the appropriate aldehyde or ketone to form ii. The compound ii maythen be saponified and reacted with amine iii, under conditions known tothose skilled in the art, to form Ia where R₂ and/or R₃ are other thanhydrogen.

Methods for preparing preferred substituents on the compounds I areillustrated in the following Schemes I to XI.

Scheme B illustrates a general method for forming compound Ib, which isa compound of formula I where Z is —CH═CH— and X₁ and X₂ together form═O. As shown in Scheme B, a 2-halo-compound vi can be prepared byreacting an appropriately substituted 2-amino-compound is with copper(ii) halide and an alkyl nitrite such as tert-butyl nitrite in anaprotic solvent such as acetonitrile to form 2-halo-compound iv (see J.Het. Chem. 22, 1621 (1985)). Compound iv can be reduced with a reducingagent such as sodium borohydride in ethanol or aqueous tetrahydrofuranto form an alcohol, which can be oxidized with an oxidizing agent suchas pyridinium chlorochromate or pyridinium dichromate to form aldehydev. Compound v can be reacted with an alkyl(triphenylphosphorylidene)acetate to form carboxylate vi. Compound vi can be saponified and thenreacted with an amine iii by methods known to those skilled in the artto form vii. Compound vii can be reacted with an amine R₂R₃NH to form Ibwhere Z is —CH═CH— and X₁, X₂ together form ═O. Alternatively, compoundsof formula Ib where R₂ and R₃ are H, can be formed by reacting compoundvii with an appropriately substituted benzyl amine such as4-methoxybenzyl amine to form compound ix, which can be hydrogenolyzedor treated with an acid such as trifluoromethanesulfonic acid andtrifluoroacetic acid in the presence of anisole to form Ib where R₂ andR₃ are hydrogen.

Methods for preparing preferred substituents on the compounds I areillustrated in the following Schemes I to XI.

Scheme C illustrates a general method for forming compound Ic, which isa compound of formula I where Z is —R₁₅C═CH— and X₁ and X₂ together form═O. As shown in Scheme C, a 2-amino-compound is can be reacted with achloroformate or dicarbonate to form x, which can be saponified andtreated with an organolithium reagent to form compound xi. Compound ximay be reacted with an alkyl(triphenylphosphorylidene)acetate, followedby deprotection of the carbamate protecting group to form xii.Alternatively, compound Ic where R₂ and R₃ are hydrogen may be formed bysaponification of xii followed by reaction with an amine R₄R₅NH bymethods known to those skilled in the art. Alternatively, compound xiimay be reacted with R₂L where L is a leaving group such as halogen (forexample, in equimolar portions), optionally followed by reaction withR₃L (for example, in equimolar portions) to form xiii, which may besaponified and reacted with an amine R₄R₅NH by methods known to thoseskilled in the art to form Ia where R₂ and/or R₃ are other thanhydrogen.

Methods for preparing preferred substituents on the compounds I areillustrated in the following Schemes I to XI.

Scheme D illustrates a general method for forming compound Id, which isa compound of the formula I where X₁ and X₂ together form ═S. Thecompounds of the formula Ia obtained in Scheme A may be converted intothe corresponding thioamide Id using a reagent such as Lawesson'sreagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (see Bull. Soc. Chim. Belg.,87, 223 (1978)).

Methods for preparing preferred substituents on the compounds I areillustrated in the following Schemes I to XI.

Scheme E illustrates a general method for forming compound Ie, which isa compound of the formula I where X₁ and X₂ are each hydrogen. As shownin Scheme E, the compound of the formula Id obtained in Scheme D may beconverted into the corresponding amine Ie by reduction, for example, byreaction with Raney nickel.

Methods for preparing preferred substituents on the compounds I areillustrated in the following Schemes I to XI.

As shown in Scheme I, carboxylate i can be reacted with a chloroformateor dicarbonate to form 1. Compound 1 can be treated with a base such assodium hydride, sodium/potassium hexamethyldisilazide, or lithiumdiisopropylamide (LDA), and an alkylating agent R₂X where X is halogenand R₂ is preferably alkyl, arylalkyl, or cycloalkylalkyl, and thensaponified with an aqueous base such as potassium hydroxide to give 2.Alternatively, 1 can the subjected to reductive amination using theappropriate aldehyde or ketone and saponified with an aqueous base suchas potassium hydroxide to give 2. Compound 1 may, alternatively, besimply saponified with an aqueous base such as potassium hydroxide togive 3 where R₂ is hydrogen.

Acid 2 may be reacted with an amine iii using reaction conditions wellknown in the art for peptide bond synthesis (see, for example, Bodanszkyand Bodanszky, The Practice of Peptide Chemistry, Springer-Verlag, 1984;Bodanszky, Principles of Peptide Synthesis, Springer-Verlag, 1984) togive the compound Id which a compound of the formula I where X₁ and X₂together form ═O, R₃ is COOR₆, and, since 2 is the starting material, R₂is preferably alkyl, arylalkyl or cycloalkylalkyl. For example, reagentswhich activate the carboxyl group of 2 for reaction with the amine ivinclude bis-(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP chloride),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP reagent), [0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium]hexafluorophosphate (HATU), and carbodiimides such asdicyclohexylcarbodiimide (DCC) or3-ethyl-3′-(dimethylamino)propylcarbodiimide (EDCI) either alone or incombination with a hydroxybenzotriazole. Alternatively, the activatedester intermediate can be isolated and then treated with the appropriateamine iv in a nonprotic solvent such as tetrahydrofuran (THF) ordimethylformamide (DMF) in the presence of a base, for example, anorganic base such as sodium/potassium hexamethyldisilazide,triethylamine, diisopropylethylamine or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or an inorganic base such assodium, potassium or cesium carbonate or sodium or potassium hydride.Alternatively, the acid halide of 2 may be prepared, for example, byreaction with thionyl chloride or oxalyl chloride, followed bysubsequent reaction with amine iii to provide compound If, which is acompound of the formula I where R₃ is COOR₆, X₁ and X₂ together form ═O,and R₂ is alkyl, arylalkyl or chycloalkylalkyl.

Similar reactions as employed above for the conversion of 2 to If may beused to convert 3 to If where R₃ is COOR₆, X₁ and X₂ together form ═O,and R₂ is hydrogen.

As shown in Scheme II, acid 4 where R₂ and R₃ are not hydrogen and areselected such that the nitrogen to which they are attached is non-basic,is reduced to the aldehyde 5 by methods well know in the art (see March,Advanced Organic Chemistry, Wiley, 1985). For example, the acid 4 may beconverted to its corresponding ester followed by reduction withdiisobutylaluminum hydride. Alternatively, the acid 4 may be reduced tothe corresponding primary alcohol, for example, by treatment withborane/THF, LiAlH₄, or via reduction of a mixed anhydride, followed bysubsequent oxidation to the aldehyde 5 using Cr(VI) (e.g., pyridiniumchlorochromate, “PCC”) or under Swern or Moffatt conditions (e.g.,(COCl)₂/dimethylsulfoxide). The starting acid 4 may be obtained, forexample, by saponification of ii.

Reductive amination (see Hudlicky, Reductions in Organic Chemistry,Wiley, 1984) of aldehyde 5 with amine iii in the presence of a reducingagent such as NaBH₃CN, NaBH(OAc)₃ (Ac=acetyl) or hydrogen and apalladium catalyst produces the amine compound Ig, which is a compoundof the formula I where X₁ and X₂ are each hydrogen and R₂ and R₃ areeach not hydrogen.

As shown in Scheme III, reduction of the acid 4 to a primary alcohol(for example, by treatment with borane/tetrahydrofuran, LiAlH₄, or viareduction of a mixed anhydride), followed by conversion by methods wellknown in the art (see March, Advanced Organic Chemistry, Wiley, 1985),provides 6 which contains a leaving group such as a halide, tosylate(OTs), mesylate (OMs) or triflate (OTf). The groups R₂ and R₃ areselected such that the resulting nitrogen to which they are attached isnon-basic. Compound 6 can then be converted into compound Ih, which is acompound of the formula I where X₁ and X₂ are each hydrogen and R₂ andR₃ are each not hydrogen, by a displacement reaction with amine iii,preferably where amine iii is used in excess.

Scheme IV illustrates methods which may be used for the preparation ofcompounds Ij, Ik, Il, Im and In. Ij, Ik, Il, Im and In are compounds ofthe formula I where R₂ is any group as defined, R₃ is an acyl orthioacyl group, X₁ and X₂ are not hydrogen, and R₁ is not a primary orsecondary amine. Ij, Ik, Il, Im and In have other particularsubstituents which are specified in this Scheme and below. The startingcompound Ii can be prepared by suitable methods described in Schemes Aand D.

Amide Ij can be prepared by treatment of amine compound Ii with acarboxylic acid 7 in the presence of reagents which activate thecarboxyl group for reaction as described above, for example BOP reagent,HATU, and carbodiimides such as DCC or EDCI either alone or incombination with a hydroxybenztriazole. Alternatively, the acid halide 8may be reacted with amine compound Ii in the presence of an acidscavenger such as diisopropylethylamine. The corresponding thioamide Ikcan be prepared by the treatment of amide Ii (where X₁,X₂≠O) withLawesson's reagent as described above.

Carbamate Il can be prepared by treatment of amine compound Ii with achloroformate 9 or dicarbonate 10 in the presence of an acid scavengersuch as diisopropylethylamine.

The urea Im may be prepared by treatment of amine compound Ii witheither: 1) a chloroformate 9, such as phenylchloroformate, followed byreaction with an amine 11; 2) a carbamoyl chloride 12 in the presence ofan acid scavenger such as diisopropylethylamine; or 3) reaction with anisocyanate 13a (where R_(c) in Im=H). The corresponding thiourea In maybe prepared by treatment of amine compound Ii with a thioisocyanate 13b.

R_(a) is selected from those groups included in the definition of R₆such that the group —C(=A)-R_(a) is an acyl or thioacyl group within thedefinition of R₃. R_(b) and R_(c) are selected from those groupsincluded in the definitions of R₇ and R₈, such that the group—C(=A)-N(R_(b))(R_(c)) is an acyl or thioacyl group within thedefinition of R₃.

Scheme V illustrates a method which can be used for the preparation ofIp, which is a compound of the formula I where R₂ is any group asdefined other than acyl, and which is selected such that the nitrogen towhich it is attached is basic, R₃ is alkyl, cycloalkyl, cycloalkylalkyl,cycloalkenylalkyl, aralkyl, or saturated heterocycle, and X₁ and X₂ arenot hydrogen. The starting compounds Io and Iq can be prepared bysuitable methods described in Schemes A and D.

As shown in Scheme V, amine compound Io is reacted with an aldehyde orketone 14 under reductive amination conditions described above to givethe amine Ip. Compound Ip may also be prepared by treatment of an aminecompound Iq, where R₂ and R₃ are hydrogen, with t-butyl nitrite orsodium nitrite in the presence of a copper (II) halide to give thehalo-substituted compound 15, followed by displacement with amine 16 inthe presence of a base such as sodium or potassium hydride or the like(see Lee et al., J. Heterocyclic Chemistry, 22, 1621 (1985)).

R_(d) and R_(e) are independently selected from hydrogen, alkyl, aryl,cycloalkyl or cycloalkenyl, or together are alkylene or alkenylenecompleting a 3- to 8-membered saturated or unsaturated ring, such thatthe group —CH(R_(d))(R_(e)) is a group within the definition of R₃.

As shown in Scheme VI, when R₂ is any group as defined other than acyl,and is selected such that the nitrogen to which it is attached is basic,R₃ is aryl or heteroaryl, and X₁ and X₂ are not hydrogen, amine compoundIr may be reacted with a halophenyl or haloheteroaromatic group 17 inthe presence of a palladium (0) catalyst (see J. Am. Chem. Soc., 118,7215 (1996)) to give amine Is, which is a compound of the formula Ihaving the particular substituents described in this Scheme. Thestarting compound Ir can be prepared by suitable methods described inSchemes A and D.

As shown in Scheme VII, when R₂ is any group as defined and R₃ is aheteroaromatic group, amine compound It may be reacted, in the presenceof a base if needed, with a 2-halosubstituted heteroaromatic compound 17where Q₁, together with atoms to which is is bonded, forms a 5- or6-membered monocyclic or 10- to 12-membered bicyclic heteroaromaticgroup (such as forming 2-chloropyridine or 2-chloropyrimidine) to givethe amine Iu, where Iu is a compound of the formula I having theparticular substituents described in this Scheme. The starting compoundIt can be prepared by suitable methods described in Schemes A and D.

As shown in Scheme VIII, thiourea compound In (where X₁ and X₂ are nothydrogen) may be reacted with the appropriate amine in the presence ofbis-(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP chloride)benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP-reagent),[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium]hexafluorophosphate(HATU) and carbodiimide, such as dicyclohexyl carbodiimide (DCC) or3-ethyl-3′-(dimethylamino)propyl carbodiimide (EDCI) or diisopropylcarbodiimide (DIC) in the presence of an organic base such astriethylamine, diisopropylethylamine or dimethylaminopyridine insolvents such as dimethylformamide, dichloromethane or tetrahydrofuranto form compound Iv, which is a compound of the formula I having theparticular substituents described in this Scheme.

Alternatively, Compound In can be reacted with the appropriate amine inthe presence of a mercury (II) salt such as mercuric chloride, or byother methods known in the literature, to form Iv.

As shown in Scheme IX, amine Ir (where X₁ and X₂ are not hydrogen) canbe reacted with diphenylcyanocarbonimidate either alone or in thepresence of a base such as sodium hydride, sodium hexamethyldisilazideor dimethylaminopyridine in acetonitrile, tetrahydrofuran, ordimethylformamide at room temperature or elevated temperature to formintermediate compound Iw. Compound Iw can be reacted with an amineR₇R₈NH to form compound Iv, which is a compound of the formula I havingthe particular substituents described in this Scheme.

As shown in Scheme X, compound Ir (where X₁ and X₂ are not hydrogen) canbe reacted with 18 or 19 either alone or in the presence of a base suchas sodium hydride, sodium hexamethyl disilazide or dimethylaminopyridinein dimethyl formamide or tetrahydrofuran at room temperature or athigher temperature to form compounds Ix or Iy respectively, which can bereacted with an amine R₇R₈NH at room temperature or elevated temperatureto form compounds Iz or Iz* respectively. Compound Iz is a compound ofthe formula I having the particular substituents described in thisScheme. Compound Iz* is a compound of the formula I having theparticular substituents described in this Scheme.

As shown in Scheme XI, compounds of formula I can also be prepared from15 by treatment with the defined amine in the presence of an acidcatalyst (for example, see: Gunzenhauser et al., Helv. Chim. Acta, 71,33 (1988)).

Utility

The compounds of the present invention inhibit protein tyrosine kinases,especially Src-family kinases such as Lck, Fyn, Lyn, Src, Yes, Hck, Fgrand Blk, and are thus useful in the treatment, including prevention andtherapy, of protein tyrosine kinase-associated disorders such asimmunologic and oncologic disorders. The compounds inhibit also receptortyrosine kinases including HER1 and HER2 and are therefore useful in thetreatment of proliferative disorders such as psoriasis and cancer. Theability of these compounds to inhibit HER1 and other receptor kinaseswill also permit their use as anti-angiogenic agents to treat disorderssuch as cancer and diabetic retinopathy. “Protein tyrosinekinase-associated disorders” are those disorders which result fromaberrant tyrosine kinase activity, and/or which are alleviated by theinhibition of one or more of these enzymes. For example, Lck inhibitorsare of value in the treatment of a number of such disorders (forexample, the treatment of autoimmune diseases), as Lck inhibition blocksT cell activation. The treatment of T cell mediated diseases, includinginhibition of T cell activation and proliferation, is a particularlypreferred embodiment of the present invention. Compounds whichselectively block T cell activation and proliferation are preferred.Compounds of the present invention which block the activation ofendothelial cell PTK by oxidative stress, thereby limiting surfaceexpression of adhesion molecules that induce neutrophil binding, andwhich inhibit PTK necessary for neutrophil activation are useful, forexample, in the treatment of ischemia and reperfusion injury.

The present invention thus provides methods for the treatment of proteintyrosine kinase-associated disorders, comprising the step ofadministering to a subject in need thereof at least one compound of theformula I in an amount effective therefor. Other therapeutic agents suchas those described below may be employed with the inventive compounds inthe present methods. In the methods of the present invention, such othertherapeutic agent(s) may be administered prior to, simultaneously withor following the administration of the compound(s) of the presentinvention.

Use of the compounds of the present invention in treating proteintyrosine kinase-associated disorders is exemplified by, but is notlimited to, treating a range of disorders such as: transplant (such asorgan transplant, acute transplant or heterograft or homograft (such asis employed in burn treatment)) rejection; protection from ischemic orreperfusion injury such as ischemic or reperfusion injury incurredduring organ transplantation, myocardial infarction, stroke or othercauses; transplantation tolerance induction; arthritis (such asrheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiplesclerosis; chronic obstructive pulmonary disease (COPD), such asemphysema; inflammatory bowel disease, including ulcerative colitis andCrohn's disease; lupus (systemic lupus erythematosis); graft vs. hostdisease; T-cell mediated hypersensitivity diseases, including contacthypersensitivity, delayed-type hypersensitivity, and gluten-sensitiveenteropathy (Celiac disease); psoriasis; contact dermatitis (includingthat due to poison ivy); Hashimoto's thyroiditis; Sjogren's syndrome;Autoimmune Hyperthyroidism, such as Graves' Disease; Addison's disease(autoimmune disease of the adrenal glands); Autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome); autoimmunealopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism;Guillain-Barre syndrome; other autoimmune diseases; cancers, includingcancers where Lck or other Src-family kinases such as Src are activatedor overexpressed, such as colon carcinoma and thymoma, and cancers whereSrc-family kinase activity facilitates tumor growth or survival;glomerulonephritis; serum sickness; uticaria; allergic diseases such asrespiratory allergies (asthma, hayfever, allergic rhinitis) or skinallergies; scleracierma; mycosis fungoides; acute inflammatory responses(such as acute respiratory distress syndrome and ishchemia/reperfusioninjury); dermatomyositis; alopecia areata; chronic actinic dermatitis;eczema; Behcet's disease; Pustulosis palmoplanteris; Pyoderma gangrenum;Sezary's syndrome; atopic dermatitis; systemic schlerosis; and morphea.The present invention also provides a method for treating theaforementioned disorders such as atopic dermatitis by administration ofany compound capable of inhibiting protein tyrosine kinase.

Src-family kinases other than Lck, such as Hck and Fgr, are important inthe Fc gamma receptor responses of monocytes and macrophages. Compoundsof the present invention inhibit the Fc gamma dependent production ofTNF alpha in the monocyte cell line THP-1 that does not express Lck. Theability to inhibit Fc gamma receptor dependent monocyte and macrophageresponses results in additional anti-inflammatory activity for thepresent compounds beyond their effects on T cells. This activity isespecially of value, for example, in the treatment of inflammatorydiseases such as arthritis or inflammatory bowel disease. In particular,the present compounds are of value for the treatment of autoimmuneglomerulonephritis and other instances of glomerulonephritis induced bydeposition of immune complexes in the kidney that trigger Fc gammareceptor responses leading to kidney damage.

In addition, Src family kinases other than Lck, such as Lyn and Src, areimportant in the Fc epsilon receptor induced degranulation of mast cellsand basophils that plays an important role in asthma, allergic rhinitis,and other allergic disease. Fc epsilon receptors are stimulated byIgE-antigen complexes. Compounds of the present invention inhibit the Fcepsilon induced degranulation responses, including in the basophil cellline RBL that does not express Lck. The ability to inhibit Fc epsilonreceptor dependent mast cell and basophil responses results inadditional anti-inflammatory activity for the present compounds beyondtheir effect on T cells. In particular, the present compounds are ofvalue for the treatment of asthma, allergic rhinitis, and otherinstances of allergic disease.

The combined activity of the present compounds towards monocytes,macrophages, T cells, etc. may be of value in the treatment of any ofthe aforementioned disorders.

In a particular embodiment, the compounds of the present invention areuseful for the treatment of the aforementioned exemplary disordersirrespective of their etiology, for example, for the treatment oftransplant rejection, rheumatoid arthritis, multiple sclerosis, chronicobstructive pulmonary disease, inflammatory bowel disease, lupus, graftv. host disease, T-cell mediated hypersensitivity disease, psoriasis,Hashimoto's thyroiditis, Guillain-Barre syndrome, cancer, contactdermatitis, allergic disease such as allergic rhinitis, asthma, ischemicor reperfusion injury, or atopic dermatitis whether or not associatedwith PTK.

By virtue of their ability to inhibit HER1 and HER2 kinases, compoundsof the present invention can also be used for the treatment ofproliferative diseases, including psoriasis and cancer. The HER1receptor kinase has been shown to be expressed and activated in manysolid tumors including non-small cell lung, colorectal, and breastcancer. Similarly, the HER2 receptor kinase has been shown to beoverexpressed in breast, ovarian, lung and gastric cancer. Monoclonalantibodies that downregulate the abundance of the HER2 receptor orinhibit signaling by the HER1 receptor have shown anti-tumor efficacy inpreclincal and clinical studies. It is therefore expected thatinhibitors of the HER1 and HER2 kinases will have efficacy in thetreatment of tumors that depend on signaling from either of the tworeceptors. These compounds are expected to have efficacy either assingle agent or in combination with other chemotherapeutic agents suchas placlitaxel (Taxol), doxorubicin hydrochloride (adriamycin), andcisplatin (Platinol). See the following documents and references citedtherein: Cobleigh, M. A., Vogel, C. L., Tripathy, D., Robert, N. J.,Scholl, S., Fehrenbacher, L., Wolter, J. M., Paton, V., Shak, S.,Lieberman, G., and Slamon, D. J., “Multinational study of the efficacyand safety of humanized anti-HER2 monoclonal antibody in women who haveHER2-overexpressing metastatic breast cancer that has progressed afterchemotherapy for metastatic disease”, J. of Clin. Oncol. 17(9), p.2639-2648 (1999); Baselga, J., Pfister, D., Cooper, M. R., Cohen, R.,Burtness, B., Bos, M., D'Andrea, G., Seidman, A., Norton, L., Gunnett,K., Falcey, J., Anderson, V., Waksal, H., and Mendelsohn, J., “Phase Istudies of anti-epidermal growth factor receptor chimeric antibody C225alone and in combination with cisplatin”, J. Clin. Oncol. 18(4), p.904-914 (2000).

The present invention also provides pharmaceutical compositionscomprising at least one of the compounds of the formula I capable oftreating a protein tyrosine kinase-associated disorder in an amounteffective therefor, and a pharmaceutically acceptable vehicle ordiluent. The compositions of the present invention may contain othertherapeutic agents as described below, and may be formulated, forexample, by employing conventional solid or liquid vehicles or diluents,as well as pharmaceutical additives of a type appropriate to the mode ofdesired administration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

The compounds of the formula I may be administered by any suitablemeans, for example, orally, such as in the form of tablets, capsules,granules or powders; sublingually; buccally; parenterally, such as bysubcutaneous, intravenous, intramuscular, or intrasternal injection orinfusion techniques (e.g., as sterile injectable aqueous or non-aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; or rectally suchas in the form of suppositories; in dosage unit formulations containingnon-toxic, pharmaceutically acceptable vehicles or diluents. The presentcompounds may, for example, be administered in a form suitable forimmediate release or extended release. Immediate release or extendedrelease may be achieved by the use of suitable pharmaceuticalcompositions comprising the present compounds, or, particularly in thecase of extended release, by the use of devices such as subcutaneousimplants or osmotic pumps. The present compounds may also beadministered liposomally.

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The present compounds may also be delivered through the oralcavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentcompound(s) with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations may also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g., Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, a suitable non-irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 0.1 to 100 mg/kg of bodyweight of active compound per day, which may be administered in a singledose or in the form of individual divided doses, such as from 1 to 4times per day. It will be understood that the specific dose level andfrequency of dosage for any particular subject may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the species, age, body weight, general health, sex and diet ofthe subject, the mode and time of administration, rate of excretion,drug combination, and severity of the particular condition. Preferredsubjects for treatment include animals, most preferably mammalianspecies such as humans, and domestic animals such as dogs, cats and thelike, subject to protein tyrosine kinase-associated disorders.

The compounds of the present invention may be employed alone or incombination with each other and/or other suitable therapeutic agentsuseful in the treatment of protein tyrosine kinase-associated disorderssuch as PTK inhibitors other than those of the present invention,antiinflammatories, antiproliferatives, chemotherapeutic agents,immunosuppressants, anticancer agents and cytotoxic agents.

Exemplary such other therapeutic agents include the following:cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such asanti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2,anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibodyOKT3, agents blocking the interaction between CD40 and gp39, such asantibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteinsconstructed from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such asnuclear translocation inhibitors, of NF-kappa B function, such asdeoxyspergualin (DSG), non-steroidal antiinflammatory drugs (NSAIDs)such as ibuprofen, steroids such as prednisone or dexamethasone, goldcompounds, antiproliferative agents such as methotrexate, FK506(tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such asazathiprine and cyclophosphamide, TNF-α inhibitors such as tenidap,anti-TNF antibodies or soluble TNF receptor such as etanercept (Enbrel),rapamycin (sirolimus or Rapamune), leflunimide (Arava), andcyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex) androfecoxib (Vioxx), or derivatives thereof, and the PTK inhibitorsdisclosed in the following U.S. patent applications, incorporated hereinby reference in their entirety: Ser. No. 60/056,770, filed Aug. 25, 1997(Attorney Docket No. QA202*), Ser. No. 60/069,159, filed Dec. 9, 1997(Attorney Docket No. QA202a*), Ser. No. 09/097,338, filed Jun. 15, 1998(Attorney Docket No. QA202b), Ser. No. 60/056,797, filed Aug. 25, 1997(Attorney Docket No. QA205*), Ser. No. 09/094,797, filed Jun. 15, 1998(Attorney Docket No. QA205a), Ser. No. 60/065,042, filed Nov. 10, 1997(Attorney Docket No. QA207*), Ser. No. 09/173,413, filed Oct. 15, 1998,(Attorney Docket No. QA207a), Ser. No. 60,076,789, filed Mar. 4, 1998(Attorney Docket No. QA208*), and Ser. No. 09,262,525, filed Mar. 4,1999 (Attorney Docket No. QA208a). See the following documents andreferences cited therein: Hollenbaugh, D., Douthwright, J., McDonald,V., and Aruffo, A., “Cleavable CD40Ig fusion proteins and the binding tosgp39”, J. Immunol. Methods (Netherlands), 188(1), p. 1-7 (Dec. 15,1995); Hollenbaugh, D., Grosmaire, L. S., Kullas, C. D., Chalupny, N.J., Braesch-Andersen, S., Noelle, R. J., Stamenkovic, I., Ledbetter, J.A., and Aruffo, A., “The human T cell antigen gp39, a member of the TNFgene family, is a ligand for the CD40 receptor: expression of a solubleform of gp39 with B cell co-stimulatory activity”, EMBO J (England),11(12), p 4313-4321 (December 1992); and Moreland, L. W. et al.,“Treatment of rheumatoid arthritis with a recombinant human tumornecrosis factor receptor (p75)-Fc fusion protein, New England J. ofMedicine, 337(3), p. 141-147 (1997).

Exemplary classes of anti-cancer agents and cytotoxic agents include,but are not limited to: alkylating agents, such as nitrogen mustards,alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes;antimetabolites, such as folate antagonists, purine analogues, andpyrimidine analogues; antibiotics, such as anthracyclines, bleomycins,mitomycin, dactinomycin, and plicamycin; enzymes, such asL-asparaginase; farnesyl-protein transferase inhibitors; hormonalagents, such as glucocorticoids, estrogens/antiestrogens,androgens/antiandrogens, progestins, and luteinizing hormone-releasinghormone anatagonists, octreotide acetate; microtubule-disruptor agents,such as ecteinascidins or their analogs and derivatives;microtubule-stabilizing agents such as paclitaxel (Taxol®), docetaxel(Taxotere®), and epothilones A-F or their analogs or derivatives;plant-derived products, such as vinca alkaloids, epipodophyllotoxins,taxanes; and topoisomerase inhibitors; prenyl-protein transferaseinhibitors; and miscellaneous agents such as, hydroxyurea, procarbazine,mitotane, hexamethylmelamine, platinum coordination complexes such ascisplatin and carboplatin; and other agents used as anti-cancer andcytotoxic agents such as biological response modifiers, growth factors;immune modulators, and monoclonal antibodies. The compounds of theinvention may also be used in conjunction with radiation therapy.

Representative examples of these classes of anti-cancer and cytotoxicagents include, but are not limited to, mechlorethamine hydrochlordie,cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan,carmustin, lomustine, semustine, streptozocin, thiotepa, dacarbazine,methotrexate, thioguanine, mercaptopurine, fludarabine, pentastatin,cladribin, cytarabine, fluorouracil, doxorubicin hydrochloride,daunorubicin, idarubicin, bleomycin sulfate, mitomycin C, actinomycin D,safracins, saframycins, quinocarcins, discodermolides, vincristine,vinblastine, vinorelbine tartrate, etoposide, teniposide, paclitaxel,tamoxifen, estramustine, estramustine phosphate sodium, flutamide,buserelin, leuprolide, pteridines, diyneses, levamisole, aflacon,interferon, interleukins, aldesleukin, filgrastim, sargramostim,rituximab, BCG, tretinoin, irinotecan hydrochloride, betamethosone,gemcitabine hydrochloride, altretamine, and topoteca and any analogs orderivatives thereof.

Preferred members of these classes include, but are not limited topaclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin,daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C,ecteinascidin 743, porfiromycin, 5-fluorouracil, 6-mercaptopurine,gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxinderivatives such as etoposide, etoposide phosphate or teniposide,melphalan, vinblastine, vincristine, leurosidine, vindesine, andleurosine.

Examples of anti-cancer and other cytotoxic agents include thefollowing: epothilone derivatives as found in U.S. Ser. No. 09/506,481filed Feb. 17, 2000 (Attorney Docket No. LD186); German Patent No.4138042.8; WO 97/19086, WO 98/22461, WO 98/25929, WO 98/38192, WO99/01124, WO 99/02224, WO 99/02514, WO 99/03848, WO 99/07692, WO99/27890, WO 99/28324, WO 99/43653, WO 99/54330, WO 99/54318, WO99/54319, WO 99/65913, WO 99/67252, WO 99/67253, and WO 00/00485; cyclindependent kinase inhibitors as found in WO 99/24416; and prenyl-proteintransferase inhibitors as found in WO 97/30992 and WO 98/54966.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

The following assays can be employed in ascertaining the degree ofactivity of a compound (“test compound”) as a PTK inhibitor. Compoundsdescribed in the following Examples have been tested in one or more ofthese assays, and have shown activity.

Enzyme Assay Using Lck, Fyn, Lyn, Hck, Fgr, Src, Blk or Yes

The following assay has been carried out using the protein tyrosinekinases Lck, Fyn, Lyn, Hck, Fgr, Src, Blk and Yes.

The protein tyrosine kinase of interest is incubated in kinase buffer(20 mM MOPS, pH7, 10 mM MgCl₂) in the presence of the test compound. Thereaction is initiated by the addition of substrates to the finalconcentration of 1 μM ATP, 3.3 μCi/ml [33P] gamma-ATP, and 0.1 mg/mlacid denatured enolase (prepared as described in Cooper, J. A., Esch, F.S., Taylor, S. S., and Hunter, T., “Phosphorylation sites in enolase andlactate dehydrogenase utilized by tyrosine protein kinases in vivo andin vitro”, J. Biol. Chem., 259, 7835-7841 (1984)). The reaction isstopped after 10 minutes by the addition of 10% trichloroacetic acid,100 mM sodium pyrophosphate followed by 2 mg/ml bovine serum albumin.The labeled enolase protein substrate is precipitated at 4 degrees,harvested onto Packard Unifilter plates and counted in a Topcountscintillation counter to ascertain the protein tyrosine kinaseinhibitory activity of the test compound (activity inverselyproportional to the amount of labeled enolase protein obtained). Theexact concentration of reagents and the amount of label can be varied asneeded.

This assay is advantageous as it employs an exogenous substrate(enolase) for more accurate enzyme kinetics, and can be conducted in a96-well format that is readily automated. In addition, His-taggedprotein tyrosine kinases (described below) offer much higher productionyields and purity relative to GST-protein tyrosine kinase fusionprotein.

The protein tyrosine kinase may be obtained from commercial sources orby recombinant methods described herewith. For the preparation ofrecombinant Lck, human Lck was prepared as a His-tagged fusion proteinusing the Life Technologies (Gibco) baculovirus vector pFastBac Hta(commercially available) in insect cells. A cDNA encoding human Lckisolated by PCR (polymerase chain reaction) was inserted into the vectorand the protein was expressed using the methods described by themanufacturer. The Lck was purified by affinity chromatography. For theproduction of Lck in insect cells using baculovirus, see Spana, C.,O'Rourke, E. C., Bolen, J. B., and Fargnoli, J., “Analysis of thetyrosine kinase p56lck expressed as a glutathione S-transferase proteinin Spodoptera frugiperda cells,” Protein expression and purification,Vol. 4, p. 390-397 (1993). Similar methods may be used for therecombinant production of other Src-family kinases.

Enzyme Assay Using HER1 or HER2

Compounds of interest were assayed in a kinase buffer that contained 20mM Tris.HCl, pH 7.5, 10 mM MnCl₂, 0.5 mM dithiothreitol, bovine serumalbumin at 0.1 mg/ml, poly(glu/tyr, 4:1) at 0.1 mg/ml, 1 μM ATP, and 4μCi/ml [gamma-³³P]ATP. Poly(glu/tyr, 4:1) is a synthetic polymer thatserves as a phosphoryl acceptor and is purchased from Sigma Chemicals.The kinase reaction is initiated by the addition of enzyme and thereaction mixtures were incubated at 26° C. for 1 h. The reaction isterminated by the addition of EDTA to 50 mM and proteins areprecipitated by the addition of trichloroacetic acid to 5%. Theprecipitated proteins are recovered by filtration onto Packard Unifilterplates and the amount of radioactivity incorporated is measured in aTopcount scintillation counter.

For the preparation of recombinant HER1, the cytoplasmic sequence of thereceptor were expressed in insect cells as a GST fusion protein, whichwas purified by affinity chromatography as described above for Lck. Thecytoplasmic sequence of HER2 was subcloned into the baculovirusexpression vector pBlueBac4 (Invitrogen) and was expressed as anuntagged protein in insect cells. The recombinant protein was partiallypurified by ion-exchange chromatography.

Cell Assays

(1) Cellular Tyrosine Phosphorylation

Jurkat T cells are incubated with the test compound and then stimulatedby the addition of antibody to CD3 (monoclonal antibody G19-4). Cellsare lysed after 4 minutes or at another desired time by the addition ofa lysis buffer containing NP-40 detergent. Phosphorylation of proteinsis detected by anti-phosphotyrosine immunoblotting. Detection ofphosphorylation of specific proteins of interest such as ZAP-70 isdetected by immunoprecipitation with anti-ZAP-70 antibody followed byanti-phosphotyrosine immunoblotting. Such procedures are described inSchieven, G. L., Mittler, R. S., Nadler, S. G., Kirihara, J. M., Bolen,J. B., Kanner, S. B., and Ledbetter, J. A., “ZAP-70 tyrosine kinase,CD45 and T cell receptor involvement in UV and H₂O₂ induced T cellsignal transduction”, J. Biol. Chem., 269, 20718-20726 (1994), and thereferences incorporated therein. The Lck inhibitors inhibit the tyrosinephosphorylation of cellular proteins induced by anti-CD3 antibodies.

For the preparation of G19-4, see Hansen, J. A., Martin, P. J., Beatty,P. G., Clark, E. A., and Ledbetter, J. A., “Human T lymphocyte cellsurface molecules defined by the workshop monoclonal antibodies,” inLeukocyte Typing I, A. Bernard, J. Boumsell, J. Dausett, C. Milstein,and S. Schlossman, eds. (New York: Springer Verlag), p. 195-212 (1984);and Ledbetter, J. A., June, C. H., Rabinovitch, P. S., Grossman, A.,Tsu, T. T., and Imboden, J. B., “Signal transduction through CD4receptors: stimulatory vs. inhibitory activity is regulated by CD4proximity to the CD3/T cell receptor”, Eur. J. Immunol., 18, 525 (1988).

(2) Calcium Assay

Lck inhibitors block calcium mobilization in T cells stimulated withanti-CD3 antibodies. Cells are loaded with the calcium indicator dyeindo-1, treated with anti-CD3 antibody such as the monoclonal antibodyG19-4, and calcium mobilization is measured using flow cytometry byrecording changes in the blue/violet indo-1 ratio as described inSchieven, G. L., Mittler, R. S., Nadler, S. G., Kirihara, J. M., Bolen,J. B., Kanner, S. B., and Ledbetter, J. A., “ZAP-70 tyrosine kinase,CD45 and T cell receptor involvement in UV and H₂O₂ induced T cellsignal transduction”, J. Biol. Chem., 269, 20718-20726 (1994), and thereferences incorporated therein.

(3) Proliferation Assays

Lck inhibitors inhibit the proliferation of normal human peripheralblood T cells stimulated to grow with anti-CD3 plus anti-CD28antibodies. A 96 well plate is coated with a monoclonal antibody to CD3(such as G19-4), the antibody is allowed to bind, and then the plate iswashed. The antibody bound to the plate serves to stimulate the cells.Normal human peripheral blood T cells are added to the wells along withtest compound plus anti-CD28 antibody to provide co-stimulation. After adesired period of time (e.g., 3 days), the [3H]-thymidine is added tothe cells, and after further incubation to allow incorporation of thelabel into newly synthesized DNA, the cells are harvested and counted ina scintillation counter to measure cell proliferation.

The following Examples illustrate embodiments of the present invention,and are not intended to limit the scope of the claims. Abbreviationsemployed in the Examples are defined below. Compounds of the Examplesare identified by the example and step in which they are prepared (forexample, “1A” denotes the title compound of step A of Example 1), or bythe example only where the compound is the title compound of the example(for example, “2” denotes the title compound of Example 2).

Abbreviations

-   aq.=aqueous-   conc.=concentrated-   DMSO=dimethylsulfoxide-   EtOAc=ethyl acetate-   Et₂O=diethyl ether-   h=hours-   HATU=N-[dimethylamino-1H-1,2,3-triazolo-[4, 5-b]pyridin-1-yl    methylene]-N-methyl methanaminium hexafluorophosphate N-oxide-   MeOH=methanol-   MOPS=4-morpholine-propanesulfonic acid-   MS=mass spectrometry-   Ret Time=retention time-   RT=room temperature-   satd.=saturated-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   DMF=N,N-dimethylformamide

Example 1 Preparation of[5-[[(2,4,6-Trimethylphenyl)amino]carbonyl]-4-methyl-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

A. Ethyl-2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate

A suspension of ethyl-2-amino-4-methyl-thiazole-5-carboxylate (18.6 g,100 mmol), di-t-butyldicarbonate (26.2 g, 120 mmol) and4-dimethylaminopyridine (800 mg, 6.55 mmol) in dry tetrahydrofuran (300mL) was stirred under nitrogen for 18 h. The solvent was evaporated invacuo. The residue was suspended in dichloromethane (1 L) and filteredthrough a pad of celite. The filtrate was washed with 1 N aqueous HClsolution (300 mL, 2×), water and brine, dried (MgSO₄), and concentratedin vacuo. The residue was triturated with hexanes. The solid wasfiltered and dried in vacuo to obtain the title compound (20 g, 72%) asa tan solid.

B. 2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylic Acid

A stirred solution ofethyl-2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate (10g, 34.95 mmol) in tetrahydrofuran-ethanol (250 mL, 2:3) was treated witha 6N KOH solution (250 mL). The mixture was heated to 55° C. overnight.The solution was cooled to 0° C. and acidified with concd. HCl to pH 1.The solvent was evaporated in vacuo. The residue was washed with water,diethyl ether, dried in vacuo over anhydrous phosphorous pentoxide toobtain the title acid (6 g, 89%) as a white solid.

C. 2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylic AcidChloride

A 2 M solution of oxalyl chloride in dichloromethane (22.5 mL, 45 mmol)was added dropwise to a stirred suspension of2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylic acid (10 g,38.72 mmol) in dichloromethane (150 mL) and N,N-dimethyl formamide (150μL) at 0° C. The suspension gradually became homogenous after additionwas complete. The solution was allowed to warm to room temperature andstirred at rt for 1.5 h. The solvent was evaporated in vacuo and theresidue was coevaporated with toluene (300 mL, 2×) and then dried invacuo to obtain the title acid chloride (10.7 g, 99%) as a tan solid.

D.[5-[[(2,4,6-Trimethylphenyl)amino]carbonyl]-4-methyl-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

2,4,6-Trimethyl aniline (6.3 mL, 38.66 mmol) was added dropwise to astirred solution of2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylic acidchloride (10.7 g, 38.66 mmol) in dichloromethane (150 mL) at 0° C. After20 min, diisopropylethylamine (8.8 mL, 44.88 mmol) was added dropwise.The solution was allowed to warm to rt and stirred for an additional 2h. The solvent was evaporated in vacuo. The residue was suspended inEtOAc (700 mL), washed with 1 N aq. HCl solution (300 mL, 2×), water,and brine; dried (MgSO₄), filtered and concentrated. The residue wastriturated with ether to obtain the title compound (12.5 g, 86%) as atan solid.

Example 2 Preparation of 2-Amino-N-(2, 4,6-trimethylphenyl)-4-methyl-5-thiazolecarboxamide

A solution of[5-[[(2,4,6-Trimethylphenyl)amino]carbonyl]-4-methyl-2-thiazolyl]carbamicacid, 1,1-dimethylethyl ester (10 g, 26.63 mmol) in trifluoroacetic acid(100 mL) was stirred at rt for 3 h. The solution was concentrated underreduced pressure and the residue was diluted with EtOAc (700 mL), washedwith 5% aq. KHCO₃ solution (400 mL, 2×), water, and brine; dried(MgSO₄), filtered and concentrated. The residue was washed with ether(200 mL) and acetonitrile (100 mL) to obtain the title compound (6.7 g,91%) as a white solid.

Example 3 Preparation of[5-[[(2,4,6-Trimethylphenyl)amino]carbonyl]-4-trifluoromethyl-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

A.Ethyl-2-tert-butoxycarbonyloxyamino-4-trifluoromethyl-thiazole-5-carboxylate

A suspension of ethyl-2-amino-4-trifluoromethyl-thiazole-5-carboxylate(5.05 g, 21.02 mmol), di-t-butyldicarbonate (4.82 g, 22.07 mmol) and4-dimethylaminopyridine (260 mg, 2.1 mmol) in dichloromethane (209 mL)was stirred under nitrogen for 1.5 h. The solvent was evaporated invacuo. The residue was chromatographed on a silica gel column. Elutionwith 5% EtOAc in hexanes, followed by 15% EtOAc in hexanes afforded thetitle compound (6.57 g, 92%) as a white solid.

B. 2-Tert-butoxycarbonyloxyamino-4-trifluoromethyl-thiazole-5-carboxylicAcid

A stirred solution ofethyl-2-tert-butoxycarbonyloxyamino-4-trifluoromethyl-thiazole-5-carboxylate(6.5 g, 19.1 mmol) in methanol (100 mL) was treated with a 1N aq. NaOHsolution (573 mL). The mixture was stirred at rt overnight. The solutionwas cooled to 0° C. and acidified with a 6 M aq. HCl solution to pH 1and extracted with chloroform (150 mL, 6×). The chloroform extracts werecombined, dried (Na₂SO₄), filtered and concentrated under reducedpressure and in vacuo to obtain the title acid (5.75 g, 96%) as a whitesolid.

C.[5-[[(2,4,6-Trimethylphenyl)amino]carbonyl]-4-trifluoromethyl-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

4-Methylmorpholine (40 μL, 0.39 mmol) was added to a mixture of2-tert-butoxycarbonyloxyamino-4-trifluoromethyl-thiazole-5-carboxylicacid (100 mg, 0.32 mmol), 2,4,6-trimethylaniline (45 μL, 0.32 mmol), andbenzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate(BOP reagent, 380 mg, 0.4 mmol) in DMF (2 mL). The solution was stirredat rt for 72 h, diluted with dichloromethane and washed with 0.25 M aq.KHSO₄ solution followed by satd. aq. KHCO₃ solution. The dichloromethaneextract was separated, dried (Na₂SO₄), filtered and concentrated. Theresidue was chromatographed on a silica gel column and eluted with 5%EtOAc in hexanes followed by 10% EtOAc in hexanes to obtain the titlecompound (90 mg, 65%) as a white solid.

Example 4 Preparation of 2-Amino-N-(2, 4,6-trimethylphenyl)-4-trifluoromethyl-5-thiazolecarboxamide,Trifluoroacetate (1:1)

A solution of[5-[[(2,4,6-Trimethylphenyl)amino]carbonyl]-4-trifluoromethyl-2-thiazolyl]carbamicacid, 1,1-dimethylethyl ester (120 mg, 0.28 mmol) in trifluoroaceticacid (5 mL) was stirred at 0° C. for 1 h. The solution was concentratedunder reduced pressure and the residue was coevaporated with ether toobtain a yellow solid which was triturated with hexanes to obtain thetitle compound (96 mg, 76%) as a light yellow solid.

Example 5 Preparation of[5-[[(2,4,6-Trimethylphenyl)amino]carbonyl]-4-phenyl-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

A. Ethyl-2-tert-butoxycarbonyloxyamino-4-phenyl-thiazole-5-carboxylate

Compound 5A was prepared by an analogous method as that of 3A, exceptusing ethyl-2-amino-4-phenyl-thiazole-5-carboxylate to give the titlecompound 5A as a white solid (90.5%).

B. 2-Tert-butoxycarbonyloxyamino-4-phenyl-thiazole-5-carboxylic Acid

Compound 5B was prepared by an analogous method as that of 3B, exceptusing 5A to give the title compound 5B as a white solid (99%).

C. 2-Tert-butoxycarbonyloxyamino-4-phenyl-thiazole-5-carboxylic AcidChloride

Compound 5C was prepared by an analogous method as that of 1C, exceptusing 5B to give the title compound 5C as a white solid (90%).

D.[5-[[(2,4,6-Trimethylphenyl)amino]carbonyl]-4-phenyl-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

Compound 5D was prepared by an analogous method as that of 1D, exceptusing 5C to give the title compound 5D as a light yellow solid (93%).

Example 6 Preparation of2-Amino-N-(2,4,6-trimethylphenyl)-4-phenyl-5-thiazolecarboxamide,Trifluoroacetate (1:1)

Compound 6 was prepared by an analogous method as that of 4, exceptusing 5D to give the title compound 6 as a white solid (68%).

Example 7 Preparation of[5-[[Phenylamino]carbonyl]-4-methyl-2-thiazolyl]carbamic Acid,1,1-dimethylethyl Ester

Compound was prepared by an analogous method as that of 1D, except usinganiline in place of 2,4,6-trimethylaniline and triethylamine in place ofdiisopropylethylamine to give the title compound 7 as an off-white solid(76%).

Example 8 Preparation of2-Amino-N-(phenyl)-4-methyl-5-thiazolecarboxamide, Trifluoroacetate(1:1)

Compound 8 was prepared by an analogous method as that of 4, exceptusing 7 to give the title compound 8 as a white solid (68%).

Example 9 Preparation of[5-[[(2,4-Dichlorophenyl)amino]carbonyl]-4-methyl-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

Compound 9 was prepared by an analogous method as that of 1D, exceptusing 2,4-dichloroaniline to give the title compound 9 as a white solid(28%).

Example 10 Preparation of2-Amino-N-(2,4-dichlorophenyl)-4-methyl-5-thiazolecarboxamide,Trifluoroacetate (1:1)

Compound 10 was prepared by an analogous method as that of 4, exceptusing 9 to give the title compound 8 as a white solid (100%).

Example 11 Preparation of5-[[(2,4,6-Trimethylphenyl)amino]carbonyl]-2-thiazolyl]carbamic Acid,1,1-dimethylethyl Ester

A. Ethyl-2-tert-butoxycarbonyloxyamino-thiazole-5-carboxylate

Compound 11A was prepared by an analogous method as that of 3A, exceptusing ethyl-2-amino-thiazole-5-carboxylate to give the title compound11A as a white solid (79.5%).

B. 2-Tert-butoxycarbonyloxyamino-thiazole-5-carboxylic Acid

Compound 11B was prepared by an analogous method as that of 3B, exceptusing 11A to give the title compound 11B as a white solid (95.5%).

C. 2-Tert-butoxycarbonyloxyamino-thiazole-5-carboxylic Acid Chloride

Compound 11C was prepared by an analogous method as that of 1C, exceptusing 11B to give the title compound 11C.

D. [5-[[(2,4,6-Trimethylphenyl)amino]carbonyl]-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

Compound 11D was prepared by an analogous method as that of 1D, exceptusing 11C to give the title compound 11D as an off-white solid (70%).

Example 12 Preparation of 2-Amino-N-(2, 4,6-trimethylphenyl)-4-phenyl-5-thiazolecarboxamide, Trifluoroacetate(1:1)

Compound 12 was prepared by an analogous method as that of 4, exceptusing 11D to give the title compound 12 as a light yellow solid (88%).

Examples 13 to 53 General Procedure

Compounds 13 to 53 were prepared following the procedure describedbelow. Appropriate amines (0.40 mmol) and diisopropylethylamine (70 μL,0.40 mmol) were added to a suspension of 1C (100 mg, 0.36 mmol) indichloromethane (3 mL). The solution was stirred mechanically in asealed tube at rt for 16 h. The reaction mixtures were diluted withmethanol (200 μL) and loaded in Varian SCX ion exchange columns (2 g/6cc) pretreated with methanol-dichloromethane (8 mL, 1:1) followed bydichloromethane (8 mL). SCX Column filtration were performed using aGilson robot unit. The column was washed sequentially withdichloromethane (9 mL), dichloromethane-methanol (9 mL, 4:1),dichloromethane-methanol (9 mL, 1:1), methanol (9 mL), 0.01 M ammoniumhydroxide in methanol (9 mL) and 0.05 M ammonium hydroxide in methanol(9 mL). The elutes were collected separately by the robot and thenconcentrated using a speed vac. Fractions containing the products werecombined.

“HPLC Ret Time” is the HPLC retention time under the followingconditions: YMC S5 ODS 4.6×50 mm Ballastic Column, 4 min gradientstarting from 100% solvent A (10% MeOH, 90% H₂O, 0.2% H₃PO₄) to 100%solvent B (90% MeOH, 10% H₂O, 0.2% H₃PO₄), flow rate 4 mL/min, λ=220 nM.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 13

[5-[[(2-Methoxy-6- methylphenyl)amino]- carbonyl]-4-methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 3.79 14

[4-Methyl-5-[[[3- methyl-4-(1-methyl- ethyl)phenyl]amino]- carbonyl]-2-thiazolyl]-carbamic acid 1,1-dimethylethyl ester 4.51 15

[5-[[(4-Bromo-2,6-di- methylphenyl)amino]- carbonyl]-4-methyl-2-thiazolyl]carbamic acid 1,1-dimethyl- ethyl ester 4.24 16

[4-Methyl-5-[[[2- methyl-6-(1- methylethyl)phenyl]- amino]carbonyl]-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 4.17 17

[5-[[(2,4- Dimethylphenyl)amino] carbonyl]-4-methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 4.05 18

[4-Methyl-5-[[(2- methylphenyl)amino] carbonyl]-2- thiazolyl]carbamicacid 1,1-dimethylethyl ester 3.87 19

[5-[[(2-Chloro-6- methylphenyl)amino] carbonyl]-4-methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 3.86 20

[5-[[[2-(1,1- Dimethylethyl)-4- methylphenyl]amino]carbonyl]-4-methyl-2- thiazolyl]carbamic acid 1,1-dimethylethyl ester4.30 21

[5-[[(2- Furanylmethyl)amino] carbonyl]-4-methyl-2- thiazolyl]carbamicacid 1,1-dimethlethyl ester 3.54 22

[5-[[(3-Methoxy-5- (trifluoromethyl)phenyl] amino]carbonyl]-4- methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 4.43 23

[5-[[(4- Cyclohexylphenyl)amino] carbonyl]-4-methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 4.78 24

[5-[[(Cyclohexyl methyl)amino]carbonyl]- 4-methyl-2-thiazolyl] carbamicacid 1,1- dimethylethyl ester 4.21 25

[5-[[(2,3-Dihydro-1H- indenyl)amino]carbonyl]- 4-methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 4.30 26

[5-[(2,5-Dihydro-1H- pyrrol-1-yl)carbonyl]- 4-methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 3.56 27

[5-[(2,5-Dihydro-2,5- dimethyl-1H-pyrrol-1- yl)carbonyl]-4-methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 3.86 28

1-[[2-[[(1,1- Dimethylethoxy)carbonyl] amino]-4-methyl-5-thiazolyl]carbonyl]-L- prolinamide 2.96 29

[5-[(4-Formyl-1- piperazinyl)carbonyl]- 4-methyl-2- thiazolyl]carbamicacid 1,1-dimethylethyl ester 2.90 30

[5-(1,4-Dioxa-8- azaspiro[4.5]decan-8- ylcarbonyl)-4-methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 3.54 31

[5-[[3-[(Diethylamino) carbonyl]-1- piperidinyl]carbonyl]-4-methyl-2-thiazolyl] carbamic acid 1,1- dimethylethyl ester 3.66 32

[4-Methyl-5- [(octahydro-1- quinolinyl)carbonyl]- 2-thiazolyl]carbamicacid 1,1-dimethylethyl ester 4.37 33

2-[[(1,1- Dimethylethoxy] carbonyl]amino]-4- methyl-5-thiazolecarboxylic acid 2-[(1,1- dimethylethoxy) carbonyl]hydrazide 3.5034

[5-[[(4-Methoxyphenyl) amino]carbonyl]-4- methyl-2- thiazolyl]carbamicacid 1,1-dimethylethyl ester 3.83 35

[4-Methyl-5-[[(4- methylphenyl)amino] carbonyl]-2- thiazolyl]carbamicacid 1,1-dimethylethyl ester 4.07 36

[5-[[(1,2- Dimethylpropyl) amino]carbonyl]-4- methyl-2-thiazolyl]carbamic acid 1,1- dimethylethyl ester 3.87 37

[5-[[(2,2- Dimethylpropyl) amino]carbonyl]-4- methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 3.97 38

[4-Methyl-5-[(2- propynylamino)carbonyl]- 2-thiazolyl]carbamic acid1,1-dimethylethyl ester 3.22 39

[4-Methyl-5-[(2- propenylamino)carbonyl]- 2-thiazolyl]carbamic acid1,1-dimethylethyl ester 3.41 40

[4-Methyl-5- [(methylphenylamino) carbonyl]-2- thiazolyl]carbamic acid1,1-dimethylethyl ester 3.75 41

[4-Methyl-5-[[(3,4,5- trimethoxyphenyl)amino] carbonyl]-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 3.84 42

[5-[[[2,6-Bis(1- methylethyl)phenyl] amino]carbonyl]-4-methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 4.40 43

[5-[[[3-(1H-Imidazol- 1-yl)propyl] amino]carbonyl]- 4-methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 2.45 44

[5-[[[(3,4- Difluorophenyl)methyl] amino]carbonyl]-4- methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 3.97 45

N-[[2-[[(1,1- Dimethylethoxy)carbonyl] amino]-4-methyl-5-thiazolyl]carbonyl]-L- leucine methyl ester 3.99 46

5-[[[2-[[(1,1- Dimethylethoxy)carbonyl] amino]-4-methyl-5-thiazolyl]carbonyl] amino]-4-oxopentanoic acid methyl ester 3.27 47

[5-[[[2-(Ethylthio) ethyl]amino]carbonyl]- 4-methyl-2-thiazolyl]carbamic acid 1,1- dimethylethyl ester 3.75 48

[5-[[Bis(3- methylbutyl)amino] carbonyl]-4-methyl-2- thiazolyl]carbamicacid 1,1-dimethylethyl ester 4.67 49

[5-[[Ethyl (1- methylethyl)amino] carbonyl]-4-methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 3.84 50

2-[[(1,1- Dimethoxyethoxy) carbonyl]amino]-4- methyl-5-thiazole-carboxylic acid 2-[[(3,5- dichlorophenyl)amino] thioxomethyl] hydrazide4.66 51

[5-[[Bis(2- ethoxyethyl)amino] carbonyl]-4-methyl-2- thiazolyl]carbamicacid 1,1-dimethylethyl ester 3.83 52

[4-Methyl-5-[[3- [(trifluoroacetyl) amino]-1- pyrrolidinyl]carbonyl]-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 3.47 53

[5-[[(2,6- Dimethylphenyl)amino] carbonyl]-4-methyl-2-thiazolyl]carbamic acid 1,1-dimethylethyl ester 3.87

Examples 54 to 129 General Procedure

Compounds 54 to 129 were prepared following the procedure describedbelow. Diisopropylethyl amine (60 μL, 0.34 mmol) was added to a mixtureof amine 2 (30 mg, 0.11 mmol), appropriate carboxylic acid (0.13 mmol),1-hydroxy-7-azabenzotriazole (19.5 mg, 0.14 mmol), andethyl-3-(3-dimethylamino)-propyl carbodiimide hydrochloride (26.8 mg,0.14 mmol) in THF (0.4 mL). The mixture was heated in a sealed tubeunder argon at 45° C. for 24 h. The reaction mixture was diluted withdichloromethane (4 mL) and washed with 2 N aq. HCl solution (2 mL, 3×).The dichloromethane solution was passed through a Varian SCX cationexchange column (2 g, 6 cc) on a Gilson robot. The column was elutedsequentially with acetonitrile-methanol (10 mL, 4:1), methanol-2Mmethanolic ammonia (3 mL, 4:1), and 2 M methanolic ammonia solution (3mL, 4×). The fractions were collected separately using the Gilson robot.Fraction containing the product was concentrated and dried in vacuo.

“HPLC Ret Time” is the HPLC retention time under the followingconditions: YMC S5 ODS 4.6×50 mm Ballastic Column, 4 min gradientstarting from 100% solvent A (10% MeOH, 90% H₂O, 0.2% H₃PO₄) to 100%solvent B (90% MeOH, 10% H₂O, 0.2% H₃PO₄), flow rate 4 mL/min, λ=220 nMfor compounds 54-127. For compounds 128-129 HPLC conditions are: ZorbaxS8-C18 4.5 mm×7.5 cm short column, 8 min gradient starting from 100%solvent A (10% MeOH, 90% H₂O, 0.2% H₃PO₄) to 100% solvent B (90% MeOH,10% H₂O, 0.2% H₃PO₄), flow rate 2.5 mL/min, λ=217 nM.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 54

2-[[(2,2-Dichloro-1- methylcyclopropyl) carbonyl]amino]- 4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.22 55

2-[(Cyclohexyl acetyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.47 56

2-[(2,5-Difluoro- benzoyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.15 57

2-[(5-Bromo-2- chlorobenzoyl)amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.37 58

2-[(3-Cyano- benzoyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.06 59

2-[[4-(Acetylamino)- benzoyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.60 60

4-Methyl-2-[[3- (trifluoromethyl) benzoyl]amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.45 61

4-Methyl-2-[[2-(2- phenylethyl)benzoyl]- amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.64 62

2-[(3,5-Dimethyl- benzoyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.49 63

2-[(4-Ethenyl- benzoyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 64

2-[(4-Butyl- benzoyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.58 65

4-Methyl-2-[(4- pentylbenzoyl)amino]- N-(2,4,6-trimethyl-phenyl)-5-thiazole- carboxamide 4.76 66

4-Methyl-2-[(2-methyl- 1-oxohexyl)amino]-N- (2,4,6-trimethyl-phenyl)-5-thiazole- carboxamide 4.41 67

4-Methyl-2-[(1-oxo-3- phenoxypropyl)amino]- N-(2,4,6-trimethyl-phenyl)-5-thiazole- carboxamide 4.21 68

4-Methyl-2-[(1-oxo-3- phenylpropyl)amino]-N- (2,4,6-trimethyl-phenyl)-5-thiazole- carboxamide 4.26 69

2-[[3-(2-Methoxy- phenyl)-1-oxopropyl]- amino]-4-methyl-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.31 70

4-Methyl-2-[(2- naphthalenylacetyl)- amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.43 71

2-[(Diphenyl- acetyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.13 72

2-[[(2-Chloro-6- fluorophenyl)acetyl]- amino]-4-methyl-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.17 73

4-Methyl-2-[[(2- methylphenyl)- acetyl]amino]-N- (2,4,6-trimethyl-phenyl)-5- thiazolecarboxamide 3.95 74

2-[[(3-Methoxy- phenyl)acetyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.11 75

2-[[(3,4-Dimethoxy- phenyl)acetyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 3.90 76

2-[[(4-Chloro- phenyl)acetyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.34 77

2-[([1,1′-Biphenyl]-4- ylacetyl)amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.60 78

4-Methyl-2-[(1-oxo-4- phenylbutyl)amino]-4- (2,4,6-trimethyl-phenyl)-5-thiazole- carboxamide 4.40 79

4-Methyl-2-[(1- oxooctyl)amino]-N- (2,4,6-trimethyl- phenyl)-5-thiazole-carboxamide 4.65 80

2-[(2-Hydroxy-2- phenyl-1- oxopropyl)amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.13 81

2-[(2-Hydroxy-1- oxohexyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.14 82

4-Methyl-2-[[1-oxo-4- (2-thienyl)- butyl]amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.32 83

4-Methyl-2-[(3- thienylcarbonyl)amino]- N-(2,4,6-trimethyl-phenyl)-5-thiazole- carboxamide 4.04 84

2-[(2-Benzofuranyl- carbonyl)amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.37 85

N-[4-Methyl-5- [[(2,4,6-trimethyl- phenyl)amino]carbonyl]-2-thiazolyl]-4- pyridinecarboxamide, N-oxide 3.50 86

6-Chloro-N-[4-methyl- 5-[[(2,4,6-trimethyl- phenyl)amino]carbonyl]-2-thiazolyl]-3- pyridinecarboxamide 4.08 87

N-[4-Methyl-5- [[(2,4,6-trimethyl- phenyl)amino]carbonyl]-2-thiazolyl]-3- pyridinecarboxamide 3.56 88

N-[4-Methyl-5- [[(2,4,6-trimethyl- phenyl)amino]carbonyl]-2-thiazolyl]-3- quinolinecarboxamide 4.11 89

4-Methyl-2-[[(4- nitrophenyl)acetyl]- amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.08 90

4-Methyl-2-[(2,4,6- trichlorobenzoyl) amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.45 91

4-Methyl-2-[[2-[[3- (trifluoromethyl)- phenyl]amino]benzoyl]-amino]-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.86 92

4-Methyl-2-[[4-(4- nitrophenyl)-1- oxobutyl]amino]-N- (2,4,6-trimethyl-phenyl)-5-thiazole- carboxamide 4.28 93

4-Methyl-2-[[4- (methyl-sulfonyl)- benzoyl]-amino]-N- (2,4,6-trimethyl-phenyl)-5-thiazole- carboxamide 3.79 94

2-[(4-Heptylbenzoyl) amino]-4-methyl-N- (2,4,6- trimethylphenyl)-5-thiazolecarboxamide 95

2-[[(2,4-Difluoro- phenyl)acetyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.15 96

(S)-2-[[2- (Dipropylamino)-1- oxopropyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 3.20 97

2-[(2-Biphenyl- enecarbonyl)amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.64 98

2-[[3-(3- Methoxyphenyl)-1- oxopropyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.26 99

4-Methyl-N-(2,4,6- trimethylphenyl)-2- [[(2,4,6-trimethyl-phenyl)acetyl]amino]- 5-thiazolecarboxamide 4.52 100

4-Methyl-2-[(1-oxo-6- heptenyl)amino]-N- (2,4,6-trimethyl-phenyl)-5-thiazole- carboxamide 4.47 101

2-[[(1,3-Benzodioxol- 5-yl)acetyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.07 102

4-Methyl-2-[[[2- (phenylmethoxy)phenyl] acetyl]amino]-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.46 103

4-Methyl-2-[[(3- phenoxyphenyl)acetyl] amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.56 104

2-[(3,5-Dimethoxy- phenyl)acetyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.13 105

2-[[4-[4-[Bis(2- chloroethyl)amino] phenyl]-1-oxobutyl]amino]-4-methyl-N- (2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.75106

4-[[4-[[[4-methyl-5- [[(2,4,6-trimethyl- phenyl)amino]carbonyl]-2-thiazolyl]-amino]- carbonyl]phenyl]- amino]-4-oxobutanoic acid methylester 4.03 107

4-Methyl-2-[[(phenyl- sulfonyl)acetyl] amino]-N-(2,4,6-trimethyl-phenyl)-5- thiazolecarboxamide 3.77 108

2-[[2-(Acetylamino)-1- oxohexyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 3.99 109

2-[[4-[(Dipropyl- amino)sulfonyl]benzoyl] amino]-4-methyl-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.51 110

2-[(4-Cyclohexyl- benzoyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.94 111

2-[(4-Bromo-3- methylbenzoyl)amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.80 112

2-[[(2,3- Difluorophenyl)acetyl] amino]-4-methyl-N- (2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.14 113

4-Methyl-2-[[[4-(1- methylethyl)phenyl] acetyl]amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.56 114

2-[[[4-(1,1-Dimethyl- ethyl)cyclohexyl] carbonyl]amino]-4-methyl-N-(2,4,6-trimethyl- phenyl)-5-thiazole carboxamide 4.85 115

N,N-Dimethyl-N′-[4- methyl-5-[[(2,4,6- trimethylphenyl)amino]carbonyl]-2- thiazolyl]butanediamide 3.50 116

2-[(1,6- Dioxohexyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.40 117

2-[(Benzo[b]thiophen- 2-ylcarbonyl)amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.53 118

2-[(1-Adamantyl- carbonyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.66 119

4-Methyl-2-[[(4- methylcyclohexyl) carbonyl]amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.48 120

2-[(1,7-Dioxooctyl)- amino]-4-methyl-N- (2,4,6-trimethyl-phenyl)-5-thiazole- carboxamide 3.88 121

2-[[2-(Acetylamino)-4- (ethylthio)-1- oxobutyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 3.93 122

1,5-Dimethyl-N-[4- methyl-5-[[(2,4,6- trimethylphenyl)amino]carbonyl]-2- thiazolyl]-1H- pyrazole-3-carboxamide 3.91 123

2-[[[4-methyl-5- [[(2,4,6-trimethylphenyl) amino]carbonyl]-2-thiazolyl]amino] carbonyl]benzoic acid 3.70 124

N-[4-Methyl-5- [[(2,4,6-trimethyl- phenyl)amino]carbonyl]-2-thiazolyl]-6-benzo- thiazolecarboxamide 4.18 125

1-Ethyl-4-methyl-N-[4- methyl-5-[[(2,4,6- trimethylphenyl)-amino]carbonyl]-2- thiazolyl]-1H- pyrazole-3-carboxamide 4.09 126

4-Methyl-2-[[3-[(3H- 1,2,3-triazolo[4,5- b]pyridin-3-yloxy)methyl]benzoyl]amino]-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.15127

2-[(2-Furanyl- carbonyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.45 128

2-[(4-Chloro- benzoyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 8.85 129

2-[(2,2-Dimethyl-1- oxopropyl)amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 8.30

Example 130 Preparation of[4-Methyl-5[[(2-nitrophenyl)amino]carbonyl]-2-thiazolyl]carbamic Acid,1,1-dimethylethyl Ester

2-Nitroaniline (55 mg, 0.4 mmol) and diisopropylethylamine (70 μL, 0.4mmol) were added dropwise to a a stirred solution of2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylic acidchloride 1C (100 mg, 0.36 mmol) in dichloromethane (3 mL). After 16 h atrt, 4-N,N-dimethylaminopyridine (22 mg, 0.18 mmol) was added and themixture was stirred for additional 3.5 h. The solvent was evaporated invacuo. The residue was chromatographed on a silica gel column. Elutionwith 5% EtOAc in hexanes followed by 20% EtOAc in hexanes afforded thetitle compound (15 mg, 11%) as a yellow solid.

Example 131 Preparation of[4-Methyl-5[[(2,4,6-trimethylphenyl)amino]carbonyl]-2-thiazolyl]carbamicAcid, Phenylmethyl Ester

A. Ethyl-2-benzyloxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate

A 3 M aq. NaHCO₃ solution (10 mL, 30 mmol) was added to a stirredsolution of ethyl-2-amino-4-methyl-thiazole-5-carboxylate (372 mg, 2mmol) in THF (20 mL) at 0-5° C. Benzyl chloroformate (500 μL) was added.After 2 h, additional benzyl chloroformate (500 μL) and the biphasicsolution was stirred for an additional 2 h at 0-5° C. The mixture wasdiluted with dichloromethane (50 mL) and water (30 mL). The organiclayer was separated, dried (MgSO₄), filtered and concentrated. Theresidue was chromatographed on a silica gel column. Elution with 10%EtOAc in hexanes followed by 20% and 30% EtOAc in hexanes afforded thetitle compound (310 mg, 48%) as a white solid.

B. 2-Benzyloxycarbonyloxyamino-4-methyl-thiazole-5-carboxylic Acid

Compound 131B was prepared by an analogous method as that of 3B, exceptusing 131A to give the title compound 131B as a white powder (77%).

C. [4-Methyl-5-[[(2, 4,6-Trimethylphenyl)amino]carbonyl]-2-thiazolyl]carbamic Acid,Phenylmethyl Ester

Diisopropylethylamine (70 μL, 0.41 mmol) was added to a solution of 131B(100 mg, 0.34 mmol), 2,4,6-trimethylaniline (60 μL, 0.41 mmol), and[O-(7-azabenzotriazol-1-yl)-1, 1, 3,3-tetramethyluronium]hexafluorophosphate (HATU, 160 mg, 0.41 mmol). Themixture was stirred at rt for 24 h, diluted with EtOAc (20 mL) andwashed with 2 N Aq. HCl solution (3×), brine, dried (Na₂SO₄), filteredand concentrated. The residue was triturated with ether (40 mL) toobtain the title compound (100 mg, 77%) as an off-white solid.

Example 132 Preparation ofMethyl[4-methyl-5-[[(2,4,6-trimethylphenyl)amino]carbonyl]-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

Compound 132 was prepared by an analogous method as that of 1, exceptusingethyl-2-tert-butoxycarbonyloxyaminomethyl-4-methyl-thiazole-5-carboxylateto give the title compound 132 as a tan solid.

Example 133 Preparation of4-Methyl-2-(methylamino)-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide,Trifluoroacetate (1:1)

Compound 133 was prepared by an analogous method as that of 4, exceptusing 132 to give the title compound 133 as a white solid (91%).

Example 134 Preparation of[4-Methyl-5-[[methyl(2,4,6-trimethylphenyl)amino]carbonyl]-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

Compound 134 was prepared by an analogous method as that of 1, exceptusing N-methyl-2,4,6-trimethylaniline to give the title compound 134 asa white solid (60%).

Example 135 Preparation of2-Amino-N,4-dimethyl-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide,Trifluoroacetate (1:1)

Compound 135 was prepared by an analogous method as that of 4, exceptusing 134 to give the title compound 135 as a white solid (97%).

Example 136 Preparation of[4-Methyl-5[[(2,4,6-trimethylphenyl)amino]carbonyl]-2-thiazolyl]carbamicAcid, Methyl Ester

A mixture of 2 (100 mg, 0.36 mmol), pyridine (87 μL, 1.08 mmol), methylchloroformate (111 μL, 1.44 mmol) in dichloromethane (3 mL) was stirredat rt for 1.5 h. The solution was diluted with dichloromethane andwashed with aq. NaHCO₃ solution (20 mL, 2×), brine; dried (MgSO₄),filtered and concentrated. The residue was triturated with ether toobtain the title compound (88 mg, 82%) as a white solid.

Example 137 Preparation of[4-Ethyl-5[[(2,4,6-trimethylphenyl)amino]carbonyl]-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

Compound 137 was prepared by an analogous method as that of 1, exceptusing methyl-2-amino-4-ethyl-thiazole-5-carboxylate to give the titlecompound 137 as a white solid (70%).

Example 138 Preparation of2-Amino-4-ethyl-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide,Trifluoroacetate

Compound 138 was prepared by an analogous method as that of 4, exceptusing 137 to give the title compound 138 as a white solid (89%).

Example 139 Preparation of[5-[[(2,6-Dichlorophenyl)amino]carbonyl]-4-methyl-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

A 1 M solution of sodium bis-trimethylsilyl amide (290 μL, 0.29 mmol)was added to a stirred solution of 2,6-dichloroaniline (13.4 mg, 0.08mmol) in THF (1 mL). After 30 min, the mixture was cooled to 0° C. and1C (30 mg, 0.11 mmol) was added in one portion. The mixture was allowedto warm to rt and stirred for 16 h. The solution was diluted withdichloromethane and washed with 2 N aq. HCl solution (2 mL, 3×), dried(MgSO₄), filtered and concentrated. The residue was chromatographed on asilica gel column and eluted with 30% EtOAc in hexanes to obtain thetitle compound (20 mg, 45%) as a light yellow solid.

Example 140 Preparation of2-Amino-N-(2,6-dimethylphenyl)-4-methyl-5-thiazolecarboxamide,Trifluoroacetate (1:1)

Compound 140 was prepared by an analogous method as that of 4, exceptusing 53 to give the title compound 140 as a light tan solid (100%).

Example 141 Preparation of2-Amino-N-(2-methoxy-6-methylphenyl)-4-methyl-5-thiazolecarboxamide,Trifluoroacetate (1:1)

Compound 141 was prepared by an analogous method as that of 4, exceptusing 13 to give the title compound 141 as an off-white solid (100%).

Example 142 Preparation of2-Amino-N-(2-methylphenyl)-4-methyl-5-thiazolecarboxamide,Trifluoroacetate (1:1)

Compound 142 was prepared by an analogous method as that of 4, exceptusing 18 to give the title compound 142 as a light tan solid (90%).

Example 143 Preparation of2-Amino-N-(2,6-dimethyl-4-bromophenyl)-4-methyl-5-thiazolecarboxamide,Trifluoroacetate (1:1)

Compound 143 was prepared by an analogous method as that of 4, exceptusing 15 to give the title compound 143 as a light tan solid (70%).

Example 144 Preparation of2-Amino-N-(2-chloro-6-methylphenyl)-4-methyl-5-thiazolecarboxamide,Trifluoroacetate (1:1)

Compound 144 was prepared by an analogous method as that of 4, exceptusing 19 to give the title compound 144 as a light tan solid (81%).

Example 145 Preparation of2-Amino-N-(2,4-dimethylphenyl)-4-methyl-5-thiazolecarboxamide,Trifluoroacetate (1:1)

Compound 145 was prepared by an analogous method as that of 4, exceptusing 17 to give the title compound 145 as a light tan solid (68%).

Example 146 Preparation of2-Amino-N-(2-methyl-6-isopropylphenyl)-4-methyl-5-thiazolecarboxamide,Trifluoroacetate (1:1)

Compound 146 was prepared by an analogous method as that of 4, exceptusing 16 to give the title compound 146 as a light tan solid (100%).

Example 147 Preparation of2-(Acetylamino)-4-methyl-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide

A mixture of 2 (54 mg, 0.2 mmol), acetic anhydride (22 μL, 0.23 mmol),dimethylaminopyridine (3 mg) in dichloromethane (4.5 mL) was stirred atrt for 4.5 h. The mixture was diluted with dichloromethane (65 mL) andwashed with 1 N aq. HCl solution (20 mL), water; dried (MgSO₄), filteredand concentrated. The residue was chromatographed on a silica gel columnand eluted with 35% EtOAc in hexanes to obtain the title compound (43mg, 69%) as a white solid.

Example 148 Preparation of2-(Benzoylamino)-4-methyl-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide

A solution of 2 (100 mg, 0.36 mmol) and benzoic anhydride (226 mg, 1mmol) in dichloromethane (10 mL) and pyridine (2 mL) was stirred at rtovernight. The mixture was diluted with dichloromethane (50 mL) andwashed with 2 N aq. HCl solution (15 mL, 2×), 10% aq. NaHCO₃ solution(20 mL, 2×); dried (MgSO₄), filtered and concentrated. The residue waschromatographed on a silica gel column and eluted with 30% EtOAc inhexanes followed by 50% EtOAc in hexanes to obtain the title compoundcontaminated with benzoic acid. The solid was dissolved in EtOAc (40 mL)and washed with satd. KHCO₃ solution (15 mL, 4×), dried (MgSO₄),filtered and concentrated to obtain the title compound (110 mg, 80%) asa white solid.

Example 149 Preparation of4-methyl-2-[(1-oxopropyl)amino]-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide

A mixture of 2 (100 mg, 0.36 mmol), propionic anhydride (332 μL, 2.58mmol) in dichloromethane (10 mL) and pyridine (4 mL) was stirred at rtfor 3 h. Dimethylaminopyridine (122 mg, 1 mmol) was added and themixture was stirred for additional 1.5 h. The mixture was diluted withdichloromethane and washed with 1 N aq. HCl solution (25 mL, 3×), aq.NaHCO3 solution (20 mL, 2×), water (20 mL), brine; dried (MgSO₄),filtered and concentrated. The residue was chromatographed on a silicagel column and eluted with 20% EtOAc in hexanes to obtain the titlecompound (81 mg, 68%) as a white solid.

Example 150 Preparation of4-methyl-2-[(1-oxobutyll)amino]-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide

Compound 150 was prepared by an analogous method as that of 149, exceptusing butyric anhydride to give the title compound 150 as a white solid(76%).

Example 151 Preparation of4-methyl-2-[(1-oxopentyl)amino]-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide

Compound 151 was prepared by an analogous method as that of 149, exceptusing valeric anhydride to give the title compound 151 as a white solid(77%).

Example 152 Preparation of4-methyl-2-[(1-oxohexyl)amino]-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide

Compound 152 was prepared by an analogous method as that of 149, exceptusing hexanoic anhydride to give the title compound 152 as a white solid(75%).

Example 153 Preparation of 4-Methyl-2-[(phenylcetyl)amino]-N-(2, 4,6-trimethylphenyl)-5-thiazolecarboxamide

A solution of amine 2 (50 mg, 0.18 mmol), diisopropylethylamine (101 μL,0.58 mmol), phenylacetic acid (27.2 mg, 0.20 mmol),1-hydroxy-7-azabenzotriazole (29.4 mg, 0.22 mmol), andethyl-3-(3-dimethylamino)-propyl carbodiimide hydrochloride (42.2 mg,0.22 mmol) in dichloromethane (0.62 mL) was mechanically stirred in asealed vial for 16 h. The reaction mixture was passed through a VarianSCX ion exchange column (2 g/6 cc) and eluted with acetonitrile-methanol(10 mL, 4:1) followed by 2 M methanolic ammonia solution (9 mL).Fractions containing the product were combined and then concentrated.The residue was dissolved in dichloromethane and washed with 2 N aq. HClsolution (3×), dried (Na₂SO₄), filtered and concentrated to obtain thetitle compound (39 mg, 55%) as a tan solid.

Example 154 Preparation of2-[[(Acetylamino)acetyl]amino]-4-methyl-N-(2,4,6-trimethylphenyl)-6-thiazolecarboxamide

A solution of amine 2 (50 mg, 0.18 mmol), diisopropylethylamine (400 μL,2.3 mmol), N-acetylglycine (42 mg, 0.36 mmol),1-hydroxy-7-azabenzotriazole (49 mg, 0.36 mmol), andethyl-3-(3-dimethylamino)-propyl carbodiimide hydrochloride (72 mg, 0.36mmol) in THF (5 mL) was heated to 50° C. overnight. The mixture wascooled, diluted with dichloromethane (60 mL) and washed with 2 N aq. HClsolution (20 mL), satd. aq. KHCO₃ solution (20 mL), dried (MgSO₄),filtered and concentrated. The crude solid was triturated with ether (10mL), filtered, and washed with ether (5 mL, 3×) to obtain the titlecompound (40 mg, 59%) as an off-white solid.

Example 155 Preparation of 2-Amino-4-methyl-N-(2, 4,6-trimethylphenyl)-5-thiazolecarbothioamide

A suspension of 2 (50 mg, 0.18 mmol) and Lawesson reagent (44 mg, 0.11mmol) in toluene (0.23 mL) was heated to 100° C. for 4 h. AdditionalLawesson reagent (44 mg, 0.11 mmol) was added and the mixture was heatedfor additional 3.5 h. The crude mixture was chromatographed on a silicagel column and eluted with 50% EtOAc in hexanes followed by 70% EtOAc inhexanes to obtain a a yellow solid which was triturated with hexanes (6mL) to obtain the title compound (11 mg, 21%) as a yellow solid.

Examples 156 to 170 General Procedure

Compounds 156 to 170 were prepared following the procedure describedbelow. Diisopropylethyl amine (60 μL, 0.34 mmol) was added to a mixtureof amine 2 (30 mg, 0.11 mmol), appropriate carboxylic acid (0.13 mmol),1-hydroxy-7-azabenzotriazole (19.5 mg, 0.14 mmol), andethyl-3-(3-dimethylamino)-propyl carbodiimide hydrochloride (26.8 mg,0.14 mmol) in THF (1 mL). The mixture was heated in a sealed tube underargon at 45° C. for 24 h. The reaction mixture was diluted withdichloromethane (4 mL) and washed with 2 N aq. HCl solution (2 mL, 3×),dried (Na₂SO₄) and concentrated using a speedvac. The crude productswere either triturated with dichloromethane-ether (5 mL, 1:1) orpurified by silica gel chromatography (elution solvent: 50% EtOAC inhexanes and EtOAc).

“HPLC Ret Time” is the HPLC retention time under the followingconditions: YMC S5 ODS 4.6×50 mm Ballastic Column, 4 min gradientstarting from 100% solvent A (10% MeOH, 90% H₂O, 0.2% H₃PO₄) to 100%solvent B (90% MeOH, 10% H₂O, 0.2% H₃PO₄), flow rate 4 mL/min, λ=220 nM.

HPLC Ret EX. Time NO. Compound Structure Compound Name (min) 156

2-[(4- Bromobenzoyl)amino]- 4-methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 5.03 157

4-Methyl-2-[(4- nitrobenzoyl)amino]-N- (2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.87 158

2-[(4- Cyanobenzoyl)amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.70 159

4-Methyl-2-[[(5-nitro- 2-furanyl)carbonyl] amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.63 160

4-Methyl-2-[(2- thienylcarbonyl)amino]- N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.60 161

4-[[[4-Methyl-5- [[(2,4,6- trimethylphenyl)amino] carbonyl]-2-thiazolyl]amino]carbonyl] benzoic acid methyl ester 4.99 162

2-[(5- Isoxazolylcarbonyl) amino]-4-methyl-N-(2, 4,6-trimethylphenyl)-5-thiazolecarboxamide 4.87 163

2-[(3-Furanylcarbonyl) amino]-4-methyl-N- (2,4,6- trimethylphenyl)-5-thiazolecarboxamide 4.54 164

2-[[(2,4-Dimethyl-5- thiazolyl)carbonyl] amino]-4-methyl-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 4.74 165

2-[[(4-Methoxy-3- thienyl)carbonyl] amino]-4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.75 166

4-Methyl-2-[[(5-nitro- 3-thienyl)carbonyl] amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.78 167

2-[[[4-[(4- Chlorophenyl)thio]-3- thienyl]carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 5.27 168

2-[[(5-Chloro-4- methoxy-3-thienyl) carbonyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 5.04 169

2-[[[2-(4,5-Dihydro- 4,4-dimethyl-2- oxazolyl)-3-thienyl]carbonyl]amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 5.13 170

2-[[(2-Acetyl-3- thienyl)carbonyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.54

Examples 171 to 180 General Procedure

Compounds 171 to 180 were prepared following the procedure describedbelow.

A mixture of 2 (80 mg, 0.29 mmol), appropriate isocyanate (0.87 mmol)and pyridine (2 mL) in THF (3.5 mL) was stirred at rt overnight. In somecases the reaction mixture was heated to 60-70° C. for 5 h. Some ofthese reactions were carried out at rt overnight in the presence ofcatalytic N,N-dimethylaminopyridine. The reaction mixture was dilutedwith dichloromethane and washed with 1 N aq. HCl solution (3×), water,brine; dried (MgSO₄), filtered and concentrated. The crude product waspurified either by trituration with ether or ether-hexanes mixture, orby chromatography on a silica gel column (elution solvent 20-40% EtOAcin hexanes) followed by trituration or by passing through Varian cationexchange SCX cartridge and sequentially eluted with methanol (5 mL),dichloromethane (5 mL), acetonitrile-methanol (10 mL, 4:1) andmethanol-2 M methanolic ammonia (10 mL, 4:1) to obtain the titlecompound.

“HPLC Ret Time” is the HPLC retention time under the followingconditions: For compounds 171-172, 175, and 177 HPLC conditions are:Zorbax S8-C18 4.5 mm×7.5 cm short column, 30 min gradient starting from100% solvent A (10% MeOH, 90% H₂O, 0.2% H₃PO₄) to 100% solvent B (90%MeOH, 10% H₂O, 0.2% H₃PO₄), flow rate 2.5 mL/min, λ=217 nM. For theother compounds HPLC conditions are: Zorbax S8-C18 4.5 mm×7.5 cm shortcolumn, 8 min gradient starting from 100% solvent A (10% MeOH, 90% H₂O,0.2% H₃PO₄) to 100% solvent B (90% MeOH, 10% H₂O, 0.2% H₃PO₄), flow rate2.5 mL/min, λ=217 nM.

HPLC Ret EX. NO. Compound Structure Compound Name Time (min) 171

4-Methyl-2-[[(methyl- amino)carbonyl]amino]- N-(2,4,6-trimethyl-phenyl)-5-thiazole- carboxamide 24.48 172

4-Methyl-2-[[(phenyl- amino)carbonyl]amino]- N-(2,4,6-trimethyl-phenyl)-5-thiazole- carboxamide 30.45 173

4-Methyl-2-[[[(4- methylphenyl)amino]- carbonyl]amino]-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide  8.81 174

4-Methyl-2-[[[(phenyl- methyl)amino]carbonyl] amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide  8.52 175

2-[[(Butylamino) carbonyl]amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 30.49 176

4-Methyl-2- [[(propylamino)carbonyl] amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide  7.41 177

2-[[(Cyclohexylamino) carbonyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 27.21 178

2-[[[(2-Chloro- phenyl)amino]carbonyl] amino]-4-methyl-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide  8.99 179

2-[[[(3-Fluorophenyl) amino]carbonyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide  8.87 180

2-[[[(2,6-Dimethyl- phenyl)amino]carbonyl] amino]-4-methyl-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide  8.92

Example 181 Preparation of[5-[[(2,4,6-Trimethylphenyl)amino]carbonyl]-4-methyl-2-thiazolyl]carbamicAcid, Phenyl Ester

A 10% aq. KHCO₃ solution (170 mL) was added to a stirred solution of 2(1.02 g, 3.7 mmol) in THF (130 mL). Phenylchloroformate (1.39 mL, 11.1mmol) was added dropwise. The biphasic mixture was stirred at rtovernight, diluted with dichloromethane (200 mL) and washed with water(50 mL, 2×) and brine. The organic extract was separated, dried (MgSO₄),filtered and concentrated. The residue was chromatographed on a silicagel column and eluted with 10% EtOAc in hexanes to obtain the titlecompound (980 mg, 69%) as a solid.

Examples 182 to 236 General Procedure

Compounds 182 to 236 were prepared following the procedure describedbelow.

A solution of phenylcarbamate 181 (20 mg, 0.054 mmol) and theappropriate amine (0.08 mmol) in THF-acetonitrile (3 mL, 1:1) wasstirred at rt overnight. Some of the reactions required heating to 60°C. for 4 h to overnight. The mixture was diluted with dichloromethane (4mL) and washed with 1 N aq. HCl solution (1.5 mL, 2×), 1 N aq. NaOHsolution (1.5 mL, 2×). The dichloromethane extract was separated, dried(MgSO₄), filtered and concentrated to obtain the title product.

“HPLC Ret Time” is the HPLC retention time under the followingconditions: For compounds 182-192 HPLC conditions are: Zorbax SB-C18 4.5mm×7.5 cm short column, 8 min gradient starting from 100% solvent A (10%MeOH, 90% H₂O, 0.2% H₃PO₄) to 100% solvent B (90% MeOH, 10% H₂O, 0.2%H₃PO₄), flow rate 2.5 mL/min, λ=217 nM. For compounds 193-236 HPLCconditions are: YMC S5 ODS 4.6×50 mm Ballastic Column, 4 min gradientstarting from 100% solvent A (10% MeOH, 90% H₂O, 0.2% H₃PO₄) to 100%solvent B (90% MeOH, 10% H₂O, 0.2% H₃PO₄), flow rate 4 mL/min, λ=220 nM.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 182

4-Methyl-2-[[[(2- phenylethyl)amino]- carbonyl]amino]-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 8.83 183

2-[[(Hexylamino) carbonyl]amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 9.01 184

2-[[[(1,1-Dimethyl- ethyl)amino]carbonyl] amino]-4-methyl-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 8.48 185

2-[[[(3-Fluoro-4- methylphenyl)amino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 8.92 186

2-[[[(4-Methoxyphenyl) amino]carbonyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 8.57 187

2-[[(Diethylamino) carbonyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 8.19 188

2-[[[Bis(1-methyl- ethyl)amino]carbonyl]- amino]-4-methyl-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 8.90 189

4-Methyl-2-[[[methyl- (phenylmethyl)amino]- carbonyl]amino]-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 8.56 190

4-Methyl-2-[[(methyl- phenylamino)carbonyl] amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 8.39 191

2-[[(Cyclohexylmethyl amino)carbonyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 8.84 192

4-Methyl-2-[[[(1- phenylethyl)amino]- carbonyl]amino]-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 8.47 193

2-[[[(Cyclopropyl- methyl)propylamino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.36 194

4-Methyl-2-[[[(2- methylcyclohexyl) amino]carbonyl]amino]-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.42 195

4-Methyl-2-[[[(4- methylcyclohexyl)- amino]carbonyl]amino]-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.49 196

2-[[[(Cyclohexyl- methyl)amino]- carbonyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.49 197

2-[[[(2,3-Dihydro-1H- inden-1-yl)amino] carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.35 198

4-Methyl-2-[[[(1- naphthalenylmethyl) amino]carbonyl]amino]-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.43 199

2-[[[Bis(phenylmethyl) amino]carbonyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.66 200

2,6-Dimethyl-N-[4- methyl-5-[[(2,4,6- trimethylphenyl)-amino]carbonyl]-2- thiazolyl]-4- morpholine- carboxamide 3.97 201

2-Ethyl-N-[4-methyl-5- [[(2,4,6-trimethyl- phenyl)amino]carbonyl]-2-thiazolyl]- 1-piperidine- carboxamide 4.29 202

1-[[[4-Methyl-5- [[(2,4,6-trimethyl- phenyl)amino]carbonyl]-2-thiazolyl]- amino]carbonyl]-3- piperidinecarboxylic acidethyl ester 4.10 203

3,3-Dimethyl-N-[4- methyl-5-[[(2,4,6- trimethylphenyl)amino]carbonyl]-2-thiazolyl]- 1-piperidine- carboxamide 4.32 204

1-[[[4-Methyl-5- [[(2,4,6-trimethyl- phenyl)amino]carbonyl]-2-thiazolyl]- amino]carbonyl]-4- piperidinecarboxylic acid ethyl ester4.06 205

4-Methyl-2-[[[(3- methyl-2-pyridinyl)- amino]carbonyl]- amino]-N-(2,4,6-trimethyl-phenyl)-5- thiazolecarboxamide 3.51 206

4-Methyl-2-[[[1- (phenylmethyl)-4- piperidinyl]amino]-carbonyl]amino]-N- (2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide3.28 207

Octahydro-N-[4-methyl- 5-[[(2,4,6-trimethyl- phenyl)amino]carbonyl]-2-thiazolyl]-1(2H)- quinolinecarboxamide 4.55 208

3,4-Dihydro-N-[4- methyl-5-[[(2,4,6- trimethylphenyl)-amino]carbonyl]-2- thiazolyl]-2(1H)- isoquinoline carboxamide 4.35 209

2-[[[(1,5-Dimethyl- hexyl)amino]carbonyl]- amino]-4-methyl-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.72 210

4-Methyl-2-[[[(1- methylheptyl)amino]- carbonyl]amino]-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.74 211

2-[[[[(2-Fluoro- phenyl)methyl]amino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.17 212

2-[[[[(2-Methoxy- phenyl)methyl]amino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.22 213

2-[[[[(2-Ethoxy- phenyl)methyl]amino] carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.36 214

2-[[[[(3-Methoxy- phenyl)methyl]amino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.13 215

2-[[[[(4-Chloro- phenyl)methyl]amino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.36 216

2-[[[[(4-Methoxy- phenyl)methyl]amino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.12 217

2-[[[(2,2-Diphenyl- ethyl)amino]carbonyl]- amino]-4-methyl-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.57 218

2-[[[(2-Aminoethyl) phenylamino]carbonyl]- amino]-4-methyl-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 3.70 219

2-[[[[2-(3-Methoxy- phenyl)ethyl]amino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.26 220

2-[[[[2-(3,4- Dimethoxyphenyl)ethyl] amino]carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.05 221

2-[[[[2-(4-Methoxy- phenyl)ethyl]amino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.25 222

4-Methyl-2-[[[(3- phenylpropyl)amino]- carbonyl]amino]-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.40 223

2-[[[[2-(Cyclohex-1- en-1-yl)ethyl]- amino]carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.11 224

2-[[[[4-(1,1- Dimethylethyl)cyclo- hexyl]amino]carbonyl]-amino]-4-methyl-N- (2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide4.85 225

2-[[[(3-Butoxypropyl) amino]carbonyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.33 226

2-[[[[2-(2-Methoxy- phenyl)ethyl]amino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.46 227

2-[[[[(2-Chloro-4- fluorophenyl)methyl]- amino]carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.39 228

2-[[(Hexylmethylamino) carbonyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.65 229

2-[[[[1-(4-Chloro- phenyl)ethyl]amino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.42 230

2-[[[[2-(3-Chloro- phenyl)ethyl]amino] carbonyl]amino]- 4-methyl-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.44 231

4-Methyl-2-[[[[2-(2- thienyl)ethyl]amino]- carbonyl]amino]-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.18 232

2-[[[[2-(2-Fluoro- phenyl)ethyl]amino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 5.85 233

4-Methyl-2-[[[[2-(2- pyridinyloxy)ethyl]- amino]carbonyl]amino]-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.28 234

2-[[[[(2-Bromo-4,5- dimethoxyphenyl) methyl]methylamino]carbonyl]amino]-4- methyl-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 3.87 235

(E)-2-[[[(3,7- Dimethyl-2,6-octa- dienyl)amino]-carbonyl]amino]-4-methyl-N- (2,4,6-trimethyl- phenyl)-5-thiazole carboxamide 4.34236

2-[[[[(2,3-Dihydro- 1,4-benzodioxin-2- yl)methyl]amino]carbonyl]amino]-4- methyl-N-(2,4,6- trimethyl-phenyl)-5-thiazole-carboxamide 4.27

Examples 237 to 285 General Procedure

Compounds 237 to 285 were prepared following the procedure describedbelow.

A solution of phenylcarbamate 181 (20 mg, 0.054 mmol) and theappropriate amine (0.08 mmol) in THF-acetonitrile (3 mL, 1:1) wasstirred at rt overnight. The mixture was diluted with dichloromethane (4mL) and washed with 1 N aq. HCl solution (1.5 mL, 2×), 1 N aq. NaOHsolution (1.5 mL, 2×). The dichloromethane extract was separated, dried(MgSO₄), filtered and concentrated to obtain the title product.

“HPLC Ret Time” is the HPLC retention time under the followingconditions: For compounds 237-278 HPLC conditions are: YMC S5 ODS 4.6×50mm Ballastic Column, 4 min gradient starting from 100% solvent A (10%MeOH, 90% H₂O, 0.2% H₃PO₄) to 100% solvent B (90% MeOH, 10% H₂O, 0.2%H₃PO₄), flow rate 4 mL/min, λ=220 nM. For compounds 279-285 HPLCconditions are: Zorbax S8-C18 4.5 mm×7.5 cm short column, 8 min gradientstarting from 100% solvent A (10% MeOH, 90% H₂O, 0.2% H₃PO₄) to 100%solvent B (90% MeOH, 10% H₂O, 0.2% H₃PO₄), flow rate 2.5 mL/min, λ=217nM.

EX. HPLC Ret NO. Compound Structure Compound Name Time (min) 237

2-[[[[3-Methoxy-5- (trifluoromethyl)phenyl] amino]carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 5.36 238

2-[[[(4-Cyclohexyl- phenyl)amino]carbonyl]- amino]-4-methyl-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 4.73 239

4-Methyl-2-[[[(5,6,7,8- tetrahydro-1- naphthalenyl)amino]-carbonyl]amino]-N- (2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 5.38240

2-[[(1-Anthracenylamino) carbonyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.82 241

2-[[[(4-Chloro-1- naphthalenyl)amino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.76 242

4-Methyl-2-[[(2- naphthalenylamino)- carbonyl]amino]-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 5.28 243

2-[[(1H-Indol-5- ylamino)carbonyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 5.00 244

2-[[(1,3-Benzodioxol-5- ylamino)carbonyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.76 245

4-Methyl-2-[[(2-pyra- zinylamino)carbonyl] amino]-N-(2,4,6-trimethyl-phenyl)-5-thiazole- carboxamide 3.84 246

2-[[[(5-Chloro-2- pyridinyl)amino]carbonyl] amino]-4-methyl-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 4.38 247

4-Methyl-2-[[[(6-methyl- 2-pyridinyl)amino]- carbonyl]amino]-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 4.44 248

4-Methyl-2-[[[(2-methyl- 4-quinolinyl)amino] carbonyl]amino]-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 5.23 249

2-[[[(2,3-Dihydro-1,4- benzodioxin-6- yl)amino]carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.72 250

2-[[([1,1′-Biphenyl]-2- ylamino)carbonyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 5.29 251

2-[[[(4-Methoxy-2- methylphenyl)amino] carbonyl]amino]-4-methyl-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 4.80 252

4-Methyl-N-(2,4,6- trimethylphenyl)-2- [[[(2,4,6-trimethylphenyl)amino]- carbonyl]amino]-5- thiazolecarboxamide 5.06 253

2-[[[[2-(2-Hydroxy- ethyl)phenyl]amino] carbonyl]amino]-4-methyl-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 4.02 254

2-[[[(3-Methoxyphenyl) amino]carbonyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.86 255

2-[[[(4-Methoxy[1,1′- biphenyl]-3- yl)amino]carbonyl]-amino]-4-methyl-N- (2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 4.81256

2-[[[(3-Acetylphenyl) amino]carbonyl]amino]- 4-methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.12 257

2-[[[(4-Cyanophenyl) amino]carbonyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.15 258

2-[[[[4-Fluoro-2- (trifluoromethyl)phenyl] amino]carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.99 259

2-[[[(4-Hexyloxyphenyl) amino]carbonyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 4.42 260

4-[[[[4-Methyl-5- [[(2,4,6-trimethyl- phenyl)amino]carbonyl]-2-thiazolyl]-amino]- carbonyl]amino] benzoic acid ethyl ester 4.26 261

2-[[[(4-Decylphenyl)- amino]carbonyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 262

4-Methyl-2-[[[(4- propylphenyl)amino]- carbonyl]amino]-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 4.71 263

4-Methyl-2-[[[(3,4,5- trimethoxyphenyl)amino]- carbonyl]amino]-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 4.67 264

4-Methyl-2-[[[[4-[[(5- methyl-3-isoxazolyl) amino]sulfonyl]phenyl]-amino]carbonyl]amino]-N- (2,4,6-trimethylphenyl)- 5-thiazolecarboxamide4.27 265

4-[[[[4-Methyl-5- [[(2,4,6-trimethyl- phenyl)amino]carbonyl]-2-thiazolyl]- amino]carbonyl]-amino]- benzoic acid butyl ester 4.75 266

2-[[(1-Isoquinolinyl amino)carbonyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 3.81 267

4-Methyl-2-[[[[2- [(phenyl-methyl)thio]- phenyl]amino]carbonyl]-amino]-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.42 268

4-Methyl-2-[[[[4-[(5- phenoxypentyl)oxy]phenyl] amino]carbonyl]amino]-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.96 269

2-[[[[5-(1,1-Dimethyl- propyl)-2-methoxy- phenyl]amino]carbonyl]-amino]-4-methyl-N- (2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 5.76270

2-[[[(1,2-Dihydro-5- acenaphthylenyl)amino] carbonyl]amino]-4-methyl-N-(2,4,6-trimethyl- phenyl)-5-thiazole- carboxamide 4.70 271

4-Methyl-2-[[[(3- phenoxyphenyl)amino]- carbonyl]amino]-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 4.70 272

4-Methyl-2-[[[[2-(4- morpholinyl)phenyl]- amino]carbonyl]amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 5.01 273

4-Methyl-2-[[[[2-(1- piperidinyl)phenyl]amino]- carbonyl]amino]-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 5.55 274

2-[[[(1-Acetyl-2,3- dihydro-1H-indol-6- yl)amino]carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 4.08 275

2-[[[(2-Bromo-5- methoxyphenyl)amino] carbonyl]amino]-4-methyl-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 4.55 276

2-[[[(2,3-Dimethyl-1H- indol-5-yl)amino]carbonyl]amino]-4-methyl-N-(2,4,6- trimethyl phenyl)-5- thiazolecarboxamide 4.30277

4-Methyl-2-[[[[2-[[(1- methylethyl)amino] carbonyl]phenyl]amino]carbonyl] amino]-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide4.82 278

2-[[[(3-Bromo-2-methyl- phenyl)amino]carbonyl]- amino]-4-methyl-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 4.60 279

2-[[[(4-Methoxybutyl) amino]carbonyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 7.62 280

2-[[[(3,3-Dimethyl- butyl)amino]carbonyl]- amino]-4-methyl-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 9.13 281

4-Methyl-2-[[[(2- methylbutyl)amino]- carbonyl]amino]-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 8.90 282

4-Methyl-2-[[[(3- methylbutyl)amino] carbonyl]amino]-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 8.98 283

2-[[[(2-Methoxyethyl)- amino]carbonyl]amino]-4- methyl-N-(2,4,6-trimethylphenyl)-5- thiazolecarboxamide 7.30 284

2-[[[[2-(Dimethyl- amino)ethyl]amino]- carbonyl]amino]-4-methyl-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide 5.73 285

4-Methyl-2-[[[[2- (methylthio)ethyl]amino] carbonyl]amino]-N-(2,4,6-trimethylphenyl)- 5-thiazolecarboxamide 8.19

Examples 286 to 311 General Procedure

Compounds 286 to 311 with the exception of compound 307 were preparedfollowing the procedure described below.

A solution of 2-[[(Butylamino)carbonyl]amino]-4-methyl-5-thiazolecarboxylic acid chloride (30 mg, 0.11 mmol), appropriate amine (0.12mmol) in THF (1 mL) was treated with diisopropylethyl amine (22.6 μL,0.13 mmol). The mixture was purged with argon and stirred mechanicallyin a vial for 22 h, diluted with dichloromethane (4 mL) and washed with2 N aq. HCl solution (3×). The organic extract was separated, dried(Na₂SO₄), filtered and concentrated. The crude products were purifiedeither by truturation with dichloromethane-ether (1:1) or by silica gelchromatography (elution solvent: 80% EtOAc in hexanes followed by EtOAc)or by automatic preparative HPLC (conditions: YMC S5 ODS A 20×100 mmColumn, 10 min gradient starting from 30% solvent B (90% MeOH, 10% H₂O,0.1% TFA) and 70% solvent A (10% MeOH, 90% H₂O, 0.1% TFA) to 100%solvent B, flow rate 20 mL/min, λ=220 nM. Compound 307 was preparedfollowing the procedure described below. A suspension solution of2-[[(Butylamino)carbonyl]amino]-4-methyl-5-thiazole carboxylic acid (100mg, 0.36 mmol), and HATU (170 mg, 0.44 mmol) in DMF (3 mL) was treatedwith diisopropylethyl amine (62 mL, 0.44 mmol). The mixture was heatedto 60° C. for 2 h, cooled, diluted with dichloromethane (12 mL), washedwith 8M aq. Urea solution in 2 N aq. HCl (6 mL, 3×), 5% aq. KHCO₃solution (6 mL, 3×), dried (Na₂SO₄), filtered and concentrated. Theresidue was triturated with EtOAc-ether to obtain the mixed anhydrideintermediate (102 mg, 74%) as a white solid. A 1 M solution of sodiumbis(trimethylsilylamide) in THF (170 μL, 0.17 mmol) was added dropwiseto a stirred solution of 2,6-dichloroaniline (19.4 mg, 0.12 mmol) in THF(1 mL). After 15 min, the mixed anhydride intermediate (41.3 mg, 0.11mmol) was added in one portion. A few drops of DMF was added and thesolution was stirred for 16 h. Additional 1 M solution of sodiumbis(trimethylsilylamide) (110 μL) was added and the mixture was stirredfor additional 2 h. The mixture was diluted with dichloromethane (4 mL)and washed with 2 N aq. HCl solution (2 mL, 3×), satd. aq. KHCO₃solution (3×), dried (Na₂SO₄), filtered and concentrated. The solid waswashed with hexanes (2×) and the residue was chromatographed on a silicagel column. Elution with 80% EtOAc in hexanes followed by EtOAc afforded307 (12 mg, 27%) as a light tan solid.

“HPLC Ret Time” is the HPLC retention time under the followingconditions: YMC S5 ODS 4.6×50 mm Ballastic Column, 4 min gradientstarting from 100% solvent A (10% MeOH, 90% H₂O, 0.2% H₃PO₄) to 100%solvent B (90% MeOH, 10% H₂O, 0.2% H₃PO₄), flow rate 4 mL/min, λ=220 nM.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 286

2-[[(Butylamino) carbonyl]amino]-N-(2,3- dihydro-1H-inden-5-yl)-4-methyl-5-thiazole- carboxamide 4.20 287

2-[[(Butylamino) carbonyl]amino]-N-2- naphthalenyl-4-methyl-5-thiazolecarboxamide 4.20 288

2-[[(Butylamino) carbonyl]amino]-N-(3- hydroxy-2-naphtha-lenyl)-4-methyl-5- thiazolecarboxamide 4.24 289

2-[[(Butylamino) carbonyl]amino]-N-(2- fluoro-5-methylphenyl)-4-methyl-5- thiazolecarboxamide 3.95 290

2-[[(Butylamino) carbonyl]amino]-N-(2,6- dimethylphenyl)-4-methyl-5-thiazole- carboxamide 3.78 291

N-(4-Bromo-2- methylphenyl)-2- [[(butylamino)carbonyl]amino]-4-methyl-5- thiazolecarboxamide 4.12 292

N-(3-Bromo-2,4,6- trimethylphenyl)-2- [[(butylamino)carbonyl]amino]-4-methyl-5- thiazolecarboxamide 4.28 293

2-[[(Butylamino) carbonyl]amino]-N-[2,6- dimethyl-3-(1-methylethyl)phenyl]-4- methyl-5- thiazolecarboxamide 4.28 294

N-(2-Bromo-4,6- dimethylphenyl)-2- [[(butylamino)carbonyl]amino]-4-methyl-5- thiazolecarboxamide 4.00 295

3-[[[2-[[(Butylamino) carbonyl]amino]-4- methyl-5-thiazolyl]-carbonyl]amino]-4- methyl-2-thiophene- carboxylic acid methyl ester 3.83296

2-[[(Butylamino) carbonyl]amino]-4- methyl-N-(2-methyl-6- quinolinyl)-5-thiazolecarboxamide 2.98 297

2-[[(Butylamino) carbonyl]amino]-N-(2,6- dimethoxyphenyl)-4-methyl-5-thiazole- carboxamide 3.39 298

2-[[(Butylamino) carbonyl]amino]-N-(4- methoxy-2-naphtha-lenyl)-4-methyl-5- thiazolecarboxamide 4.31 299

2-[[(Butylamino) carbonyl]amino]-N-(2- methyl-1-naphthalenyl)-4-methyl-5-thiazole- carboxamide 3.92 300

2-[[(Butylamino) carbonyl]amino]-N-[4- (dimethylamino)-2,3,5,6-tetramethyl- phenyl]-4-methyl-5- thiazolecarboxamide 3.14 301

2-[[(Butylamino) carbonyl]amino]-N-(6- methyl-5-quinolinyl)-4- methyl-5-thiazolecarboxamide 3.13 302

2-[[(Butylamino) carbonyl]amino]-N-[2- (2-hydroxyethyl)-6-methylphenyl]-4-methyl- 5-thiazolecarboxamide 3.50 303

2-[[(Butylamino) carbonyl]amino]-N-(2,6- dimethyl-3-nitrophenyl)-4-methyl- 5-thiazolecarboxamide 3.75 304

N-(2-Bromo-3,4,6- trimethylphenyl)-2- [[(butylamino)carbonyl]amino]-4-methyl-5- thiazolecarboxamide 4.12 305

N-(2-Acetyl-6- hydroxyphenyl)-2- [[(butylamino)carbonyl]amino]-4-methyl-5- thiazolecarboxamide 3.75 306

[4-[[[2-[[(Butylamino) carbonyl]amino]-4- methyl-5-thiazolyl]-carbonyl]amino]- 2,3,5,6-tetramethyl- phenyl]carbamic acid1,1-dimethylethyl ester 4.10 307

2-[[(Butylamino) carbonyl]amino]-N-(2,6- dichlorophenyl)-4- methyl-5-thiazolecarboxamide 4.42 308

N-(4-Amino-2,3,5,6- tetramethylphenyl)-2- [[(butylamino)carbonyl]amino]-4-methyl-5- thiazolecarboxamide 3.15 309

N-[5-(Acetylamino)-2,4- dimethylphenyl]-2- [[(butylamino)carbonyl]amino]-4-methyl-5- thiazolecarboxamide 3.52 310

N-(4-Bromo-2,6- dimethylphenyl)-2- [[(butylamino)carbonyl]amino]-4-methyl-5- thiazolecarboxamide 4.93 311

2-[[(Butylamino) carbonyl]amino]-N-(2- chloro-6-methylphenyl)-4-methyl-5- thiazolecarboxamide 4.51

Example 312 Preparation of4-Methyl-2-[(methylsulfonyl)amino]-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide

A. Ethyl-2-[(methylsulfonyl)amino]-4-methyl-thiazole-5-carboxylate

A stirred solution of ethyl-2-amino-4-methyl-thiazole-5-carboxylate (558mg, 3 mmol) in dichloromethane (15 mL) and pyridine (5 mL) was treatedwith methanesulfonyl chloride (687 mg, 6 mmol) at rt overnight. Thesolution was diluted with dichloromethane (50 mL) and washed with 2N aq.HCl solution (15 mL, 3×), dried (MgSO₄), filtered and concentrated. Thecrude residue was diluted with ether (25 mL) and the solid was filtered,washed with 1:1 ether:hexane mixture (10 mL, 3×), and dried in vacuo toobtain the title compound (687 mg, 87%) as an off-white solid.

B. 2-[(Methylsulfonyl)amino]-4-methyl-thiazole-5-carboxylic Acid

A stirred solution ofEthyl-2-[(methylsulfonyl)amino]-4-methyl-thiazole-5-carboxylate (300 mg,1.14 mmol) in methanol (9 mL) was treated with a 1N NaOH solution (28.4mL, 28.4 mmol). The mixture was stirred at rt overnight. The solutionwas cooled to 0 DC and acidified with 6N aq. HCl solution to pH 1. Thesolution was extracted with dichloromethane-chloroform mixture. Theorganic extract was dried (MgSO4), filtered and concentrated in vacuo toobtain the title acid (148 mg, 55%).

C.4-Methyl-2-[(methylsulfonyl)amino]-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide

Diisopropylethylamine (87 μL, 0.5 mmol) was added to a solution of 312 B(99 mg, 0.42 mmol), 2,4,6-trimethylaniline (68 μL, 0.5 mmol), and[O-(7-azabenzotriazol-1-yl)-1, 1, 3,3-tetramethyluronium]hexafluorophosphate (HATU, 191 mg, 0.5 mmol) in DMF(3 mL). The mixture was stirred at rt overnight, diluted with EtOAc andwashed with 0.5 N aq. HCl solution (15 mL), 10% aq. LiCl solution (25mL, 3×), water (930 mL, 2×), brine, dried (MgSO₄), filtered andconcentrated. The residue was chromatographed on a silica gel column andeluted with 50% EtOAc in hexanes, followed by 75% EtOAc in hexanes and2% MeOH in EtOAc to obtain the title compound (19 mg, 13%) as a whitesolid.

Example 313 Preparation of4-Methyl-2-[[(phenylamino)thiocarbonyl]amino)-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide

A solution of 2 (45 mg, 0.16 mmol) and phenylisothiocyanate (43 mg, 0.32mmol) in pyridine (2 mL) was heated to 80° C. for 20 h. The mixture wascooled, diluted with dichloromethane-THF mixture (80 mL, 3:1) and washedwith 2 N aq. HCl solution (15 mL, 2×). The organic extract was dried(MgSO₄), filtered and concentrated. The residue was diluted with EtOAc(20 mL) and the solid was filtered, washed with ether (10 mL, 3×), anddried in vacuo to obtain the title compound (35 mg, 52%) as an off-whitesolid.

Example 314 Preparation of2-[[(Ethylamino)carbonyl]amino]-4-methyl-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide

Compound 314 was prepared by an analogous method as that of compounds171-180, using ethylisocyanate to give the title compound 314 as a whitesolid (65%).

Example 315 Preparation ofN-(2-Chloro-6-methylphenyl)-2-[(cyclopropylcarbonyl)amino]-5-thiazolecarboxamide

A. Ethyl-2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate

A suspension of ethyl-2-amino-thiazole-5-carboxylate (972 mg, 6 mmol, B.Plouvler, C. Bailly, R. Houssin, j-P. Henlchart Heterocyles 32(4),693-701, 1991 and H. J. Becker, J. de Jonge Rec. Tray. Chim, 61, 463,1942), di-t-butyldicarbonate (1.94 g, 9 mmol) and4-dimethylaminopyridine (73 mg, 0.6 mmol) in dry tetrahydrofuran (75 mL)was stirred under nitrogen for 24 h. The solvent was evaporated invacuo. The residue was suspended in ether (50 mL). The solid was washedwith ether (10 mL, 3×), and dried in vacuo to obtain the title compound(1.1 g, 70%).

B. 2-tert-butoxycarbonyloxyamino-thiazole-5-carboxylic Acid

A stirred solution ofethyl-2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate (1.1g, 4.2 mmol) in tetrahydrofuran-methanol (80 mL, 1:1) was treated with a6N aq. NaOH solution (20 mL, 120 mmol). The mixture was stirred at rtfor 24 h. Most of THF and methanol were removed by distillation underreduced pressure and the aq. Solution was acidified with 6 N aq. HClsolution (22 mL). The precipitated solid was filtered, washed with waterand ether, air dried followed by drying in vacuo to obtain the titleacid (940 mg, 96%) as an off-white solid.

C. [5-[[(2-chloro-6-methylphenyl)amino]carbonyl]-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

A 2 M solution of oxalyl chloride in dichloromethane (1 mL, 2 mmol) wasadded dropwise to a stirred solution of2-tert-butoxycarbonyloxyamino-thiazole-5-carboxylic acid (234 mg, 1mmol) in THF (10 mL) and N,N-dimethyl formamide (few drops). Thesolution was stirred at rt for 4 h. The solvent was evaporated underreduced pressure, and in vacuo to obtain the crude acid chloride.

2-Chloro-6-methyl aniline (212 mg, 1.5 mmol) was added dropwise to astirred solution of crude2-tert-butoxycarbonyloxyamino-thiazole-5-carboxylic acid chloride (1mmol) in dichloromethane (10 mL) at 0° C.

Diisopropylethylamine (516 mg, 4 mmol) was added. The solution wasallowed to warm to rt and stirred for 24 h, diluted with dichloromethane(60 mL) and washed with 2 N aq. HCl solution (15 mL). The organicextract was dried (MgSO₄), filtered and concentrated. The residue wasdiluted with EtOAc-ether (25 mL, 1:4) and the solid was filtered andwashed with ether (5 mL, 4×), and dried in vacuo to obtain the titlecompound (175 mg, 48%) as a tan solid.

D. 2-Amino-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide

Compound 315D was prepared by an analogous method as that of 2, exceptusing compound 315C to give the title compound 315D as a tan solid.

E.2-[(Cyclopropylcarbonyl)amino]-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide

A solution of 315D (50.6 mg, 0.19 mmol) and cyclopropanecarboxylic acidanhydride (302 mg, 1.96 mmol) in dioxane (2 mL) was heated to 93° C.overnight. The mixture was concentrated in vacuo, diluted with EtOAc andwashed with satd. aq. KHCO₃ solution (2×). The organic extract was dried(Na₂SO₄), filtered and concentrated. The residue was triturated withether to obtain the title compound (11 mg, 17%) as a white solid.

Example 316 Preparation of2-[[[(1,1-Dimethylethyl)amino]carbonyl]amino]-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide

Sodium hydride (19.2 mg, 0.8 mmol) was added to a solution of 315D (48.3mg, 0.18 mmol) and t-butylisocyanate (41 μL, 0.36 mmol) in THF (5 mL) at0° C. After 1 h, the mixture was diluted with EtOAc and washed with coldsatd. aq. ammonium chloride solution. The aqueous layer was separatedand extracted with EtOAc. The EtOAc extracts were combined, dried(Na₂SO₄), filtered and concentrated. The residue was purified byautomatic preparative HPLC (conditions: YMC S5 ODS A 20×100 mm Column,10 min gradient starting from 10% solvent B (90% MeOH, 10% H2O, 0.1%TFA) and 90% solvent A (10% MeOH, 90% H2O, 0.1% TFA) to 100% solvent B,flow rate 20 mL/min, λ=220 nM to obtain the title compound (18 mg, 28%)as an off-white solid.

Example 317 Preparation of2-[[(1,1-Dimethylethoxy)carbonyl]amino]-4-methyl-N-(2,4,6-trimethylphenyl)-5-thiazoleacetamide

Compound 317 was prepared by an analogous method as that of 1, exceptusing methyl-2-amino-4-methyl-thiazole-5-acetate to give the titlecompound 317 as an off-white solid.

Example 318 Preparation of 2-Amino-4-methyl-N-(2, 4,6-trimethylphenyl)-5-thiazoleacetamide

Compound 318 was prepared by an analogous method as that of 2, exceptusing 317 to give the title compound 318 as a light brown solid.

Example 319 Preparation ofN-(2-Chloro-6-methylphenyl)-2-[(4,6-dimethyl-2-pyridinyl)amino]-5-thiazolecarboxamide

A. 2-Bromo-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide

A solution of copper (II) bromide (2.68 g, 12 mmol) in acetonitrile (50mL) was purged with nitrogen and cooled to 0° C. t-Butyl nitrite (2 mL,15 mmol) was added, followed by a solution of compound 315D (2.68 g, 10mmol) in acetonitrile (50 mL), The mixture was stirred at rt overnightand concentrated in vacuo. The residue was dissolved in EtOAc, washedwith satd. aq. NaHCO₃ solution and the precipitate was removed byfiltration. The organic extract was dried (Na₂SO₄), filtered andconcentrated. The residue was crystallized from EtOAc/ether/hexanesmixture to obtain the title compound (1.68 g, 51%) as a yellow solid.

B.N-(2-Chloro-6-methylphenyl)-2-[(4,6-dimethyl-2-pyridinyl)amino]-5-thiazolecarboxamide

95% Sodium hydride (15 mg) was added to a mixture of 319A (25 mg, 0.075mmol) and 4,6-dimethyl-2-aminopyridine (37 mg, 0.302 mmol) in THF (1mL). The mixture was heated to 60° C. overnight, cooled to rt anddiluted with satd. aq. ammonium chloride solution. The mixture wasextracted with EtOAc (2×). Organic extracts were combined, washed withwater and dried (Na₂SO₄), filtered and concentrated. The residue wastriturated with ether to obtain the title compound (17.5 mg, 63%) as atan solid.

Example 320 Preparation ofN-(2-Chloro-6-methylphenyl)-2-[(4-ethyl-2-pyridinyl)amino]-5-thiazolecarboxamide

Compound 320 was prepared by an analogous method as that of 319B, exceptusing 4-ethyl-2-aminopyridine to give the title compound 320.

Example 321 Preparation ofN-(2-Chloro-6-methylphenyl)-2-[(2,6-dimethyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide

Compound 321 was prepared by an analogous method as that of 319B, exceptusing 2,6-dimethyl-4-aminopyrimidine to give the title compound 321.

Example 322 Preparation ofN-(2-Chloro-6-methylphenyl)-2-(3-pyridazinylamino)-5-thiazolecarboxamide

Compound 322 was prepared by an analogous method as that of 319B, exceptusing 3-aminopyridazine to give the title compound 322.

Examples 323 to 335 General Procedure

Compounds 323 to 335 were prepared following the procedure describedbelow. Diisopropylethyl amine (60 μL, 0.34 mmol) was added to a mixtureof amine 144 (31 mg, 0.11 mmol), appropriate carboxylic acid (0.13mmol), 1-hydroxy-7-azabenzotriazole (19.5 mg, 0.14 mmol), andethyl-3-(3-dimethylamino)-propyl carbodiimide hydrochloride (26.8 mg,0.14 mmol) in THF (0.4 mL). The mixture was heated in a sealed tubeunder argon at 50° C. for 24 h. The reaction mixture was diluted withdichloromethane (4 mL) and washed with 1 N aq. HCl solution. Thedichloromethane solution was passed through a Varian Mega Bond Elut SCXcation exchange column (prewashed with methanol and equilibrated withacetonitrile-methanol (4:1). The column was eluted sequentially withacetonitrile-methanol (4:1), methanol-2M methanolic ammonia (4:1).Fractions containing the product were combined and concentrated invacuo.

“HPLC Ret Time” is the HPLC retention time under the followingconditions: YMC S5 ODS 4.6×50 mm Ballastic Column, 4 min gradientstarting from 100% solvent A (10% MeOH, 90% H2O, 0.2% H3PO4) to 100%solvent B (90% MeOH, 10% H2O, 0.2% H3PO4), flow rate 4 mL/min, λ=220 nM.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 323

N-(2-Chloro-6-methylphenyl)-4- methyl-2-[(2-thienyl- carbonyl)amino]-5-thiazolecarboxamide 3.70 324

N-(2-Chloro-6-methylphenyl)-2- [(cyclopropylcarbonyl)amino]-4-methyl-5-thiazolecarboxamide 3.41 325

N-(2-Chloro-6-methylphenyl)-4- methyl-2-[(2-furanyl- carbonyl)amino]-5-thiazolecarboxamide 3.49 326

N-(2-Chloro-6-methylphenyl)-4- methyl-2-[(3-thienyl-carbonyl)amino]-5-thiazole- carboxamide 3.71 327

N-(2-Chloro-6-methylphenyl)-4- methyl-2-[(3- furanylcarbonyl)amino]-5-thiazolecarboxamide 3.57 328

trans-N-(2-Chloro-6- methylphenyl)-4-methyl-2-[[(2-phenylcyclopropyl)carbonyl] amino]-5-thiazolecarboxamide 4.09 329

N-(2-Chloro-6-methylphenyl)-4- methyl-2-[[(2-methylcyclo-propyl)carbonyl]amino]-5- thiazolecarboxamide 3.65 330

N-(2-Chloro-6-methylphenyl)-2- [(cyclobutylcarbonyl)amino]-4-methyl-5-thiazolecarboxamide 3.63 331

N N-(2-Chloro-6-methylphenyl)- 2-[(cyclopentylcarbonyl)amino]-4-methyl-5-thiazolecarboxamide 3.82 332

N-(2-Chloro-6-methylphenyl)-4- methyl-2-[(2-methyl-1-oxopropyl)amino]-5- thiazolecarboxamide 3.50 333

N-(2-Chloro-6-methylphenyl)-4- methyl-2-[(1-oxopentyl)amino]-5-thiazolecarboxamide 3.79 334

N-(2-Chloro-6-methylphenyl)-4- methyl-2-[(2-methyl-1-oxopentyl)amino]-5- thiazolecarboxamide 3.90 335

2-(Benzoylamino)-N-(2-chloro-6- methylphenyl)-4-methyl-5-thiazolecarboxamide 3.79

Examples 336 to 362 General Procedure

Compounds 336 to 362 were prepared by an analogous method as that of323-335, except using 315D in place of 144. The crude products werepurified by automatic preparative HPLC (conditions: YMC S5 ODS A 20×100mm Column, 10 min gradient starting from 10% solvent B (90% MeOH, 10%H2O, 0.1% TFA) and 90% solvent A (10% MeOH, 90% H2O, 0.1% TFA) to 100%solvent B, flow rate 20 mL/min, λ=220 nM to obtain the title compounds336-362.

“HPLC Ret Time” is the HPLC retention time under the followingconditions: YMC S5 ODS 4.6×50 mm Ballastic Column, 4 min gradientstarting from 100% solvent A (10% MeOH, 90% H2O, 0.2% H3PO4) to 100%solvent B (90% MeOH, 10% H2O, 0.2% H3PO4), flow rate 4 mL/min, λ=220 nM.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 336

N-(2-Chloro-6-methylphenyl)-2- [(1-oxopropyl)amino]-5-thiazolecarboxamide 3.53 337

N-(2-Chloro-6-methylphenyl)-2- [(1-oxobutyl)amino]-5-thiazolecarboxamide 3.61 338

N-(2-Chloro-6-methylphenyl)-2- [(2-ethyl-1-oxobutyl)amino]-5-thiazolecarboxamide 3.54 339

N-(2-Chloro-6-methylphenyl)-2- [[(1-phenylcyclo-propyl)carbonyl]amino]-5- thiazolecarboxamide 3.86 340

N-(2-Chloro-6-methylphenyl)-2- [[(1-methylcyclo-propyl)carbonyl]amino]-5- thiazolecarboxamide 3.53 341

N-(2-Chloro-6-methylphenyl)-2- [[(2,2-dichloro-1-methylcyclo-propyl)carbonyl]amino]-5- thiazolecarboxamide 3.53 342

N-(2-Chloro-6-methylphenyl)-2- [[(2-methylcyclo-propyl)carbonyl]amino]-5- thiazolecarboxamide 3.53 343

N-(2-Chloro-6-methylphenyl)-2- [[(1-hydroxycyclopropyl)-carbonyl]amino]-5-thiazole- carboxamide 3.58 344

N-(2-Chloro-6-methylphenyl)-2- [[(2,2,3,3-tetramethylcyclo-propyl)carbonyl]amino]-5- thiazolecarboxamide 3.69 345

N-(2-Chloro-6-methylphenyl)-2- [[(1-cyanocyclopropyl)-carbonyl]amino]-5-thiazole- carboxamide 3.53 346

N-(2-Chloro-6-methylphenyl)-2- [(cyclobutylcarbonyl)amino]-5-thiazolecarboxamide 3.52 347

N-(2-Chloro-6-methylphenyl)-2- [(cyclopentylcarbonyl)amino]-5-thiazolecarboxamide 3.59 348

N-(2-Chloro-6-methylphenyl)-2- [(cyclohexylcarbonyl)amino]-5-thiazolecarboxamide 3.78 349

N-(2-Chloro-6-methylphenyl)-2- [(phenylacetyl)amino]-5-thiazolecarboxamide 3.62 350

N-(2-Chloro-6-methylphenyl)-2- [(cyclohexylacetyl)amino]-5-thiazolecarboxamide 4.07 351

N-(2-Chloro-6-methylphenyl)-2- [(4-pyridinylacetyl)amino]-5-thiazolecarboxamide 3.75 352

N-(2-Chloro-6-methylphenyl)-2- [[(2,5-dimethyl-1H-pyrrol-3-yl)carbonyl]amino]-5- thiazolecarboxamide 3.17 353

N-(2-Chloro-6-methylphenyl)-2- [(2-pyridinylcarbonyl)amino]-5-thiazolecarboxamide 3.07 354

N-(2-Chloro-6-methylphenyl)-2- [(3-pyridinylcarbonyl)amino]-5-thiazolecarboxamide 3.07 355

N-(2-Chloro-6-methylphenyl)-2- [(4-pyridinylcarbonyl)amino]-5-thiazolecarboxamide 3.61 356

N-(2-Chloro-6-methylphenyl)-2- [(3-thienylcarbonyl)amino]-5-thiazolecarboxamide 3.60 357

N-(2-Chloro-6-methylphenyl)-2- [(2-thienylcarbonyl)amino]-5-thiazolecarboxamide 3.61 358

N-(2-Chloro-6-methylphenyl)-2- [(2-furanylcarbonyl)amino]-5-thiazolecarboxamide 3.61 359

N-(2-Chloro-6-methylphenyl)-2- [(3-furanylcarbonyl)amino]-5-thiazolecarboxamide 3.69 360

trans-N-(2-Chloro-6- methylphenyl)-2-[[(2- phenylcyclopropyl)carbonyl]amino]-5-thiazolecarboxamide 3.98 361

N-(2-Chloro-6-methylphenyl)-2- [(2-methyl-1-oxopentyl)amino]-5-thiazolecarboxamide 3.90 362

2-(Benzoylamino)-N-(2-chloro-6- methylphenyl)-5- thiazolecarboxamide3.61

Example 363 Preparation of2-[(Cyclopropylcarbonyl)amino]-N-(2,6-dimethylphenyl)-5-thiazolecarboxamide

Compound 363 was prepared by an analogous method as that of 315, exceptusing 2,6-dimethylaniline to give the title compound 363.

Example 364 Preparation of2-[(Cyclopropylcarbonyl)amino]-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide

Compound 364 was prepared by an analogous method as that of 315, exceptusing 2,4,6-trimethylaniline to give the title compound 364.

Example 365 Preparation ofN-(2-Chloro-4,6-dimethylphenyl)-2-[(cyclopropylcarbonyl)amino]-5-thiazolecarboxamide

Compound 365 was prepared by an analogous method as that of 315, exceptusing 2-chloro-4,6-dimethylaniline to give the title compound 365.

Example 366 Preparation of[4-[2-Oxo-2-[(2,4,6-trimethylphenyl)amino]ethyl]-2-thiazolyl]carbamicAcid 1,1-dimethylethyl Ester

Compound 366 was prepared by an analogous method as that of 1 except,using 2-tert-butoxycarbonyloxyamino-thiazole-4-acetic acid to give thetitle compound 366 as a white solid.

Example 367 Preparation of2-Amino-N-(2,4,6-trimethylphenyl)-4-thiazoleacetamide

Compound 367 was prepared by an analogous method as that of 4, exceptusing 365 to give the title compound 367 as a white solid.

Example 368 Preparation of2-Methyl-5-nitro-N-(2,4,6-trimethylphenyl)benzamide

Compound 368 was prepared by an analogous method as that of 3, exceptusing 2-methyl-5-nitrobenzoic acid to give the title compound 368 as awhite solid.

Example 369 Preparation of 5-Amino-2-methyl-N-(2, 4,6-trimethylphenyl)benzamide

10% Palladium on charcoal (30 mg) was added to a stirred solution of 368(149 mg, 0.5 mmol) in EtOAc (50 mL). The reaction flask was equippedwith a hydrogen filled balloon via a three-way stopcock. Air inside theflask was evacuated under reduced pressure and the flask filled withhydrogen from the balloon. After 4 h, the catalyst was filtered, washedwith EtOAc (5 mL, 5×). The filtrate was concentrated to obtain the titlecompound (133 mg, 99%) as a white solid.

Example 370 Preparation of2-Amino-5-chloro-N-(2,4,6-trimethylphenyl)-4-pyrimidinecarboxamide

Compound 370 was prepared by an analogous method as that of 3, exceptusing 2-amino-5-chloro-pyrimidine-4-carboxylic acid to give the titlecompound 370 as a white solid.

Example 371 Preparation of[4-Methyl-5-[[(2,4,6-trimethylphenyl)amino]carbonyl]-2-oxazolyl]carbamicAcid 1,1-dimethylethyl Ester

Compound 371 was prepared by an analogous method as that of 1, exceptusing 2-tert-butoxycarbonyloxyamino-4-methyl-5-oxazolecarboxylic acid togive the title compound 371 as a light yellow foam.

Example 372 Preparation of 2-Amino-4-(methyl)-N-(2, 4,6-trimethylphenyl)-5-oxazolecarboxamide, Trifluoroacetate (1:1)

Compound 372 was prepared by an analogous method as that of 4, exceptusing 369 to give the title compound 372 as a white solid.

Example 373 Preparation of2-Amino-N-(2,4,6-trimethylphenyl)-5-pyridinecarboxamide

Compound 373 was prepared by an analogous method as that of 3, exceptusing 6-aminonicotinic acid to give the title compound 373 as a whitesolid.

Example 374 Preparation 3-Amino-N-(2, 4,6-trimethylphenyl)-4-pyridinecarboxamide

Compound 374 was prepared by an analogous method as that of 3, exceptusing 3-amino-4-pyridinecarboxylic acid to give the title compound 374as a white solid.

Example 375 Preparation 2-Amino-4-methyl-N-(2, 4,6-trimethylphenyl)-5-pyrimidinecarboxamide

Compound 375 was prepared by an analogous method as that of 3, exceptusing 2-amino-4-methyl-5-pyrimidinecarboxylic acid to give the titlecompound 375 as a white solid.

Example 376 Preparation ofN-(2-Chloro-6-methylphenyl)-2-[(4-methyl-2-pyridinyl)amino]-5-thiazolecarboxamide

Compound 376 was prepared by an analogous method as that of 319B, exceptusing 2-amino-4-methyl-pyridine to give the title compound 376 as anoff-white solid.

Example 377 Preparation of2-[(6-Amino-2-pyridinyl)amino]-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide

Compound 377 was prepared by an analogous method as that of 319B, exceptusing 2,6-diaminopyridine to give the title compound 377 as a lightbrown solid solid.

Example 378 Preparation ofN-(2-Chloro-6-methylphenyl)-2-[(6-propyl-2-pyridinyl)amino]-5-thiazolecarboxamide

Compound 378 was prepared by an analogous method as that of 319B, exceptusing 2-amino-6-propyl-pyridine to give the title compound 378 as anoff-white solid.

Example 379 Preparation ofN-(2-Chloro-6-methylphenyl)-2-[(6-ethyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide

Compound 379 was prepared by an analogous method as that of 319B, exceptusing 4-amino-6-ethyl-pyrimidine to give the title compound 379 as awhite solid.

Examples 380 to 409 General Procedure

Compounds 380 to 409 were prepared by an analogous method as that of319B. For the following examples 380 to 527 “HPLC Ret Time” is the HPLCretention time under the following conditions: YMC S5 ODS 4.6×50 mmBallastic Column, 4 min gradient starting from 100% solvent A (10% MeOH,90% H₂O, 0.2% H₃PO₄) to 100% solvent B (90% MeOH, 10% H₂O, 0.2% H₃PO₄),flow rate 4 mL/min, λ=220 nM. Where used, “HPLC Ret Time ‘B’” is theHPLC retention time under the following conditions: YMC S5 ODS 4.6×33 mmTurbo Column, 2 min gradient starting from 100% solvent A (10% MeOH, 90%H₂O, 0.1% TFA) to 100% solvent B (90% MeOH, 10% H₂O, 0.1% TFA) with 1min at 100% solvent B, flow rate 4 mL/min, λ=220 nM.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 380

′N-(2-Chloro-6-methylphenyl)-2- (2-pyridinylamino)-5-thiazolecarboxamide 3.337 381

′N-(2-Chloro-6-methylphenyl)-2- [(6-methyl-2-pyridinyl)amino]-5-thiazolecarboxamide 3.61 382

′N-(2-Chloro-6-methylphenyl)-2- [(5-methyl-2-pyridinyl)amino]-5-thiazolecarboxamide 3.487 383

′N-(2-Chloro-6-methylphenyl)-2- [(4-methyl-2-pyridinyl)amino]-5-thiazolecarboxamide 3.293 384

′N-(2-Chloro-6-methylphenyl)-2- [(3-methyl-2-pyridinyl)amino]-5-thiazolecarboxamide 3.243 385

′2-[(5-Bromo-3-methyl-2- pyridinyl)amino]-N-(2-chloro-6-methylphenyl)-5- thiazolecarboxamide 4.17 386

′2-[(6-Amino-2-pyridinyl)amino]- N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide 2.817 387

′2-[(5-Bromo-2-pyridinyl)amino]- N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide 4.023 388

′N-(2-Chloro-6-methylphenyl)-2- [[3-(phenylmethoxy)-2-pyridinyl]amino]-5- thiazolecarboxamide 4.143 389

′N-(2-Chloro-6-methylphenyl)-2- [(5-chloro-2-pyridinyl)amino]-5-thiazolecarboxamide 3.957 390

′N-(2-Chloro-6-methylphenyl)-2- [(6-ethyl-2-pyridinyl)amino]-5-thiazolecarboxamide 3.867 391

′N-(2-Chloro-6-methylphenyl)-2- [(6-propyl-2-pyridinyl)amino]-5-thiazolecarboxamide 4.083 392

′2-[(3-Bromo-5-methyl-2- pyridinyl)amino]-N-(2-chloro-6-methylphenyl)-5- thiazolecarboxamide 4.077 393

′2-[(2-Amino-3-pyridinyl)amino]- N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide 2.343 394

′2-[(3-Amino-2-pyridinyl)amino]- N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide 2.777 395

′N-(2-Chloro-6-methylphenyl)-2- (4-pyridinylamino)-5-thiazolecarboxamide 2.493 396

′N-(2-Chloro-6-methylphenyl)-2- (3-pyridinylamino)-5-thiazolecarboxamide 2.47 397

′N-(2-Chloro-6-methylphenyl)-2- [(6-chloro-3-pyridinyl)amino]-5-thiazolecarboxamide 3.75 398

′N-(2-Chloro-6-methylphenyl)-2- [(2-chloro-3-pyridinyl)amino]-5-thiazolecarboxamide 3.443 399

′N-(2-Chloro-6-methylphenyl)-2- [(6-methoxy-3-pyridinyl)amino]-5-thiazolecarboxamide 3.517 400

′N-(2-Chloro-6-methylphenyl)-2- [(3,5-dimethyl-2- pyrazinyl)amino]-5-thiazolecarboxamide 3.583 401

′N-(2-Chloro-6-methylphenyl)-2- (phenylamino)-5- thiazolecarboxamide3.697 402

′N-(2-Chloro-6-methylphenyl)-2- [(3-ethylphenyl)amino]-5-thiazolecarboxamide 4.107 403

′N-(2-Chloro-6-methylphenyl)-2- [(3,5-dimethylphenyl)amino]-5-thiazolecarboxamide 3.98 404

′N-(2-Chloro-6-methylphenyl)-2- [(4,6-dimethyl-2- pyrimidinyl)amino]-5-thiazolecarboxamide 3.51 405

′N-(2-Chloro-6-methylphenyl)-2- [(6-ethyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide 2.943 406

′N-(2-Chloro-6-methylphenyl)-2- [(6-chloro-2-pyrazinyl)amino]-5-thiazolecarboxamide 3.763 407

′2-[(3-Aminophenyl)amino]-N-(2- chloro-6-methylphenyl)-5-thiazolecarboxamide 2.633 408

′N-(2-Chloro-6-methylphenyl)-2- [(3-hydroxyphenyl)amino]-5-thiazolecarboxamide 3.337 409

′2-[(3-Bromophenyl)amino]-N-(2- chloro-6-methylphenyl)-5-thiazolecarboxamide 4.12

Example 410 Preparation of′N-(2,6-Dimethylphenyl)-2-(phenylamino)-5-thiazolecarboxamide

A. [5-[[(2,6-dimethylphenyl)amino]carbonyl]-2-thiazolyl]carbamic Acid,1,1-dimethylethyl Ester

Compound 410A was prepared by an analogous method as that of 315C,except using 2,6-dimethylaniline.

B. 2-Amino-N-(2,6-dimethylphenyl)-5-thiazolecarboxamide

Compound 410B was prepared by an analogous method as that of 315D,except using compound 410A.

C. Title Compound

The title compound was prepared by an analogous method as that of 319B,except using compound 410B and aniline. HPLC Ret. Time 3.69 min.

Examples 411 to 427 General Procedure

Compounds 411 to 427 were prepared by an analogous method as that of319B.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 411

′N-(2,6-Dimethylphenyl)-2- (methylphenylamino)-5- thiazolecarboxamide3.667 412

′N-(2,6-Dimethylphenyl)-2-(2- pyridinylamino)-5- thiazolecarboxamide3.297 413

′N-(2,6-Dimethylphenyl)-2-[(6- methyl-2-pyridinyl)amino]-5-thiazolecarboxamide 3.587 414

′N-(2,6-Dimethylphenyl)-2-[(4- methyl-2-pyridinyl)amino]-5-thiazolecarboxamide 3.222 415

′N-(2,6-Dimethylphenyl)-2-[(4- ethyl-2-pyridinyl)amino]-5-thiazolecarboxamide 3.54 416

′N-(2,6-Dimethylphenyl)-2-[(4,6- dimethyl-2-pyridinyl)amino]-5-thiazolecarboxamide 3.543 417

′2-[(6-Amino-2-pyridinyl)amino]- N-(2,6-dimethylphenyl)-5-thiazolecarboxamide 2.807 418

′N-(2,6-Dimethylphenyl)-2-[(6- ethyl-2-pyridinyl)amino]-5-thiazolecarboxamide 3.847 419

′N-(2,6-Dimethylphenyl)-2-[(6- propyl-2-pyridinyl)amino]-5-thiazolecarboxamide 4.057 420

′2-[(2-Amino-3-pyridinyl)amino]- N-(2,6-dimethylphenyl)-5-thiazolecarboxamide 2.337 421

′2-[(3-Amino-2-pyridinyl)amino]- N-(2,6-dimethylphenyl)-5-thiazolecarboxamide 2.737 422

′2-[(6-Amino-2-methyl-4- pyrimidinyl)amino]-N-(2,6- dimethylphenyl)-5-thiazolecarboxamide 2.71 423

′N-(2,6-Dimethylphenyl)-2-[[6-(4- morpholinyl)-3- pyridazinyl]amino]-5-thiazolecarboxamide 2.727 424

′2-[(6-Chloro-3- pyridazinyl)amino]-N-(2,6- dimethylphenyl)-5-thiazolecarboxamide 3.46 425

′N-(2,6-Dimethylphenyl)-2-(3- pyridazinylamino)-5- thiazolecarboxamide2.973 426

′2-[(3-Aminophenyl)amino]-N- (2,6-dimethylphenyl)-5- thiazolecarboxamide2.63 427

′2-[(3-Bromophenyl)amino]-N- (2,6-dimethylphenyl)-5- thiazolecarboxamide4.143

Example 428 Preparation of′2-(2-Pyridinylamino)-N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide

A. [5-[[(2,4,6-trimethylphenyl)amino]carbonyl]-2-thiazolyl]carbamicAcid, 1,1-dimethylethyl Ester

Compound 428A was prepared by an analogous method as that of 315C,except using 2,4,6-trimethylaniline.

B. 2-Amino-N-(2,6-dimethylphenyl)-5-thiazolecarboxamide

Compound 428B was prepared by an analogous method as that of 315D,except using compound 428A.

C. Title Compound

The title compound was prepared by an analogous method as that of 319B,except using compound 428B and 2-aminopyridine. HPLC Ret. Time 3.66 min.

Examples 429 to 443 General Procedure

Compounds 429 to 443 were prepared by an analogous method as that of319B.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 429

′2-[(6-Methyl-2-pyridinyl)amino]-N- (2,4,6-trimethylphenyl)-5-thiazolecarboxamide 3.903 430

′2-[(5-Methyl-2-pyridinyl)amino]-N- (2,4,6-trimethylphenyl)-5-thiazolecarboxamide 3.8 431

′2-[(4-Methyl-2-pyridinyl)amino]-N- (2,4,6-trimethylphenyl)-5-thiazolecarboxamide 3.603 432

′2-[(3-Methyl-2-pyridinyl)amino]-N- (2,4,6-trimethylphenyl)-5-thiazolecarboxamide 3.56 433

′2-[(5-Bromo-2-pyridinyl)amino]-N- (2,4,6-trimethylphenyl)-5-thiazolecarboxamide 4.263 434

′2-[(5-Chloro-2-pyridinyl)amino]-N- (2,4,6-trimethylphenyl)-5-thiazolecarboxamide 4.203 435

′2-[(6-Methoxy-3-pyridinyl)amino]- N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide 3.8 436

′2-[(4-Ethyl-2-pyridinyl)amino]-N- (2,4,6-trimethylphenyl)-5-thiazolecarboxamide 3.86 437

′2-[(6-Ethyl-2-pyridinyl)amino]-N- (2,4,6-trimethylphenyl)-5-thiazolecarboxamide 4.127 438

′2-[(6-Chloro-3-pyridinyl)amino]-N- (2,4,6-trimethylphenyl)-5-thiazolecarboxamide 4.017 439

′2-[(2,6-Dimethyl-4- pyrimidinyl)amino]-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 2.943 440

′2-[(4-Methyl-2-pyrimidinyl)amino]- N-(2,4,6-trimethylphenyl)-5-thiazolecarboxamide 3.723 441

′2-(2-Pyrazinylamino)-N-(2,4,6- trimethylphenyl)-5- thiazolecarboxamide3.65 442

′2-[(6-Chloro-2-pyrazinyl)amino]-N- (2,4,6-trimethylphenyl)-5-thiazolecarboxamide 4.05 443

′2-[(3,5-Dimethyl-2- pyrazinyl)amino]-N-(2,4,6- trimethylphenyl)-5-thiazolecarboxamide 3.877

Example 444 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[[2-methyl-6-[[2-(4-morpholinyl)ethyl]amino]-4-pyrimidinyl]amino]-5-thiazolecarboxamide

A

To a suspension of NaH (148 mg, 6.17 mmol) in THF (20 mL) was added asolution of compound 315D (551 mg, 2.06 mmol) in THF (10 mL) and stirredat RT for 0.5 h. A solution of 4,6-dichloro-2-methylpyrimidine (671.6mg, 4.12 mmol) in THF (10 mL) and stirred at RT overnight. The reactionwas quenched with acetic acid and the solvent removed in vacuo. Waterand saturated NaHCO₃ were added to the residue and extracted withCH₂Cl₂. The organic layer was removed in vacuo and the crude materialpurified by column chromatography to give 444A (494 mg).

B. Title Compound

To compound 444A (30 mg) was added N-(2-aminoethyl)-morpholine (3004)and the mixture was heated at 80° C. for 2 h. Water was added to thereaction and the product was collected by filtration. HPLC Ret. Time2.357 min.

Examples 445 to 461 General Procedure

Compounds 445 to 461 were prepared by an analogous method as that of444B by substituting the appropriate amine.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 445

′N-(2-Chloro-6-methylphenyl)-2- [[2-methyl-6-[[3-(4-morpholinyl)propyl]amino]-4- pyrimidinyl]amino]-5- thiazolecarboxamide2.253 446

′N-(2-Chloro-6-methylphenyl)-2-[[2- methyl-6-[methyl[3-(methyl-amino)propyl]amino]-4- pyrimidinyl]amino]-5-thiazole- carboxamide 2.493447

′N-(2-Chloro-6-methylphenyl)-2- [[2-methyl-6-[[2-(tetrahydro-2-oxo-1H-imidazol-1-yl)ethyl]-amino]-4- pyrimidinyl]amino]-5-thiazole-carboxamide 2.71  448

′N-(2-Chloro-6-methylphenyl)-2- [[2-methyl-6-[(2-1H-imidazol-4-ylethyl)amino]-4- pyrimidinyl]amino]-5- thiazolecarboxamide 2.303 449

′N-(2-Chloro-6-methylphenyl)-2- [[2-methyl-6-(4-morpholinyl)-4-pyrimidinyl]amino]-5- thiazolecarboxamide 3.337 450

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[[(2R)-1-ethyl-2-pyrrolidinyl]methyl]amino]-2- methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide 2.703 451

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]amino]-2- methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide 2.717 452

′2-[[6-[(2S)-2-(Aminocarbonyl)-1- pyrrolidinyl]-2-methyl-4-pyrimidinyl]amino]-N-(2-chloro-6- methylphenyl)-5- thiazolecarboxamide2.81  453

′N-(2-Chloro-6-methylphenyl)-2- [[6-[(2-hydroxyethyl)amino]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide 2.677 454

′N-(2-Chloro-6-methylphenyl)-2- [[6-[4-(hydroxymethyl)-1-piperidinyl]-2-methyl-4- pyrimidinyl]amino]-5- thiazolecarboxamide 3.05 455

′N-(2-Chloro-6-methylphenyl)-2- [[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5- thiazolecarboxamide 2.717456

′1-[6-[[5-[[(2-Chloro-6- methylphenyl)amino]carbonyl]-2-thiazolyl]amino]-2-methyl-4- pyrimidinyl]-4- piperidinecarboxamide 2.863457

′N-(2-Chloro-6-methylphenyl)-2- [[2-methyl-6-[(3S)-3-methyl-1-piperazinyl]-4-pyrimidinyl]amino]- 5-thiazolecarboxamide 2.823 458

′2-[[6-[3-(Acetylamino)-1- pyrrolidinyl]-2-methyl-4-pyrimidinyl]amino]-N-(2-chloro-6- methylphenyl)-5- thiazolecarboxamide2.78  459

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[2-(1-methyl-2-pyrrolidinyl)ethyl]amino]-2-methyl- 4-pyrimidinyl]amino]-5-thiazolecarboxamide 2.383 460

′N-(2-Chloro-6-methylphenyl)-2- [[2-methyl-6-[[(5-methyl-2-pyrazinyl)methyl]amino]-4- pyrimidinyl]amino]-5- thiazolecarboxamide3.027 461

′N-(2-Chloro-6-methylphenyl)-2- [[2-methyl-6-[[2-(1H-1,2,3-triazol-1-yl)ethyl]amino]-4- pyrimidinyl]amino]-5- thiazolecarboxamide 2.78 

Example 462 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[[6-[[2-(4-morpholinyl)ethyl]amino]-4-pyrimidinyl]amino]-5-thiazolecarboxamide

A

Compound 462A was prepared by an analogous method as that of 444A,except using 4,6-dichloropyrimidine.

B. Title Compound

The title compound was prepared by an analogous method as that of 444B,except using compound 462A in place of compound 444A. HPLC Ret. Time2.553 min.

Examples 463 to 472 General Procedure

Compounds 463 to 472 were prepared by an analogous method as that of444B by substituting the appropriate amine. “HPLC Ret Time ‘B’” is theHPLC retention time under the following conditions: YMC S5 ODS 4.6×33 mmTurbo Column, 2 min gradient starting from 100% solvent A (10% MeOH, 90%H₂O, 0.1% TFA) to 100% solvent B (90% MeOH, 10% H₂O, 0.1% TFA) with 1min at 100% solvent B, flow rate 4 mL/min, λ=220 nM.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 463

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[2-(dimethyl-amino)-ethyl]amino]-4-pyrimidinyl]- amino]-5-thiazolecarboxamide 2.527 464

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[2-(tetrahydro-2-oxo-1H-imidazol-1-yl)ethyl]amino]-4- pyrimidinyl]amino]-5- thiazolecarboxamide2.797 465

′N-(2-Chloro-6-methylphenyl)-2- [[6-[methyl[2-(methylamino)-ethyl]amino]-4-pyrimidinyl]- amino]-5-thiazolecarboxamide 1.137 B 466

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[2-(1-methyl-2-pyrrolidinyl)ethyl]amino]-4- pyrimidinyl]amino]-5- thiazolecarboxamide1.113 B 467

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[2-(1-pyrrolidinyl)-ethyl]amino]-4-pyrimidinyl]- amino]-5-thiazolecarboxamide 1.150 B 468

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[(1-ethyl-2-pyrrolidinyl)methyl]amino]-4- pyrimidinyl]amino]-5- thiazolecarboxamide 1.237 B 469

′N-(2-Chloro-6-methylphenyl)-2- [[6-[(4-piperidinyl- methyl)amino]-4-pyrimidinyl]amino]-5- thiazolecarboxamide 1.160 B 470

′2-[[6-[[2-(Acetylamino)- ethyl]amino]-4- pyrimidinyl]amino]-N-(2-chloro-6- methylphenyl)-5-thiazole- carboxamide 2.457 B 471

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[2-(1H-1,2,3-triazol-1-yl)ethyl]amino]-4- pyrimidinyl]amino]-5- thiazolecarboxamide 2.897 472

′N-(2-Chloro-6-methylphenyl)-2- [[6-(4-morpholinyl)-4-pyrimidinyl]amino]-5- thiazolecarboxamide 3.437

Example 473 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[[6-[[2-(4-morpholinyl)ethyl]amino]-2-pyridinyl]amino]-5-thiazolecarboxamide

A

To a suspension of NaH (2.83 g, 118 mmol) in DMF (350 mL) cooled to 000was added compound 319A (31 g, 93.5 mmol). The mixture was stirred for45 min at 000 then Bu₄NI (6.9 g, 18.7 mmol) was added followed byaddition of 4-methoxy benzylchloride (18 g, 115 mmol). The reaction wasallowed to warm to RT. After stirring overnight at RT the reaction wasquenched slowly with acetic acid then the solvent removed in vacuo. Tothe residue was added water and neutralized with saturated aqueousNaHCO₃. The mixture was extracted 3 times with EtOAc and the combinedorganic layers washed with water then washed with saturated NaClsolution. The EtOAc layer was concentrated in vacuo and the residuepurified by column chromatography to give 473A (35 g).

B

To compound 473A (0.5 g, 1.1 mmol) dissolved in THF (50 mL) was slowlyadded NaH (0.13 g, 5.5 mmol) followed by 2-bromo-6-aminopyridine (0.76g, 4.4 mmol). The reaction was heated to reflux for 2 h then cooled toRT and quenched with acetic acid. The solvent was removed in vacuo thenwater and hexane was added and stirred at RT. The solid precipitate wascollected by filtration and washed with water and Et₂O to give 473B(0.48 g)

C

To compound 473B (0.48 g) dissolved in TFA (5 mL) was added anisole (2mL) followed by triflic acid (1 mL). The reaction was stirred at RT for3 h then was slowly added to a rapidly stirred mixture of ice, saturatedNaHCO₃, Et₂O and CH₂Cl₂. The mixture was stirred cold for 1 h then thesolid precipitate was collected by filtration and washed with waterfollowed by Et₂O/CH₂Cl₂ mixture to give 473C (0.344 g). HPLC Ret. Time3.85 min.

D. Title Compound

The title compound was prepared by an analogous method as that of 444B,except using compound 473C in place of compound 444A. HPLC Ret. Time2.80 min.

Examples 474 to 480 General Procedure

Compounds 474 to 480 were prepared by an analogous method as that of473D by substituting the appropriate amine.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 474

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[3-(4-morpholinyl)-propyl]amino]-2-pyridinyl]- amino]-5-thiazolecarboxamide 2.867 475

′N-(2-Chloro-6-methylphenyl)-2- [[6-[methyl[3-(methyl-amino)propyl]amino]-2- pyridinyl]amino]-5-thiazole- carboxamide 3.067476

′N-(2-Chloro-6-methylphenyl)-2- [[6-[(3S)-3-methyl-1-piperazinyl]-2-pyridinyl]-amino]-5- thiazolecarboxamide 2.827 477

′N-(2-Chloro-6-methylphenyl)-2- [[6-[(3-1H-imidazol-1-ylpropyl)amino]-2-pyridinyl]- amino]-5-thiazolecarboxamide 2.83  478

′N-(2-Chloro-6-methylphenyl)-2- [[6-[(2-hydroxyethyl)amino]-2-pyridinyl]amino]-5- thiazolecarboxamide 3.077 479

′N-(2-Chloro-6-methylphenyl)-2- [[6-[(2-1H-imidazol-1-ylethyl)amino]-2-pyridinyl]- amino]-5-thiazolecarboxamide 2.903 480

′N-(2-Chloro-6-methylphenyl)-2- [[6-(4-morpholinyl)-2-pyridinyl]amino]-5- thiazolecarboxamide 3.727

Example 481 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[[6-[[2-(4-morpholinyl)ethyl]amino]-2-pyrazinyl]amino]-5-thiazolecarboxamide

A

Compound 481A was prepared by an analogous method as that of 473B,except using compound 2-chloro-6-aminopyrazine in place of compound2-bromo-6-aminopyridine.

B. (Alternate Synthesis for Compound 406)

Compound 406 was prepared by an analogous method as that of 473C, exceptusing compound 481A in place of compound 473B.

C. Title Compound

The title compound was prepared by an analogous method as that of 444B,except using compound 406 in place of compound 444A. HPLC Ret. Time 2.69min.

Examples 482 to 486 General Procedure

Compounds 482 to 486 were prepared by an analogous method as that of481C by substituting the appropriate amine.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 482

′N-(2-Chloro-6-methylphenyl)- 2-[[6-[[3-(4-morpholinyl)-propyl]amino]-2-pyrazinyl]- amino]-5-thiazolecarboxamide 2.783 483

′N-(2-Chloro-6-methylphenyl)- 2-[[6-(4-morpholinyl)-2-pyrazinyl]amino]-5-thiazole- carboxamide 3.57  484

′N-(2-Chloro-6-methylphenyl)- 2-[[6-[(3S)-3-methyl-1-piperazinyl]-2-pyrazinyl]- amino]-5-thiazolecarboxamide 2.743 485

′N-(2-Chloro-6-methylphenyl)- 2-[[6-(3-hydroxy-1-pyrrolidinyl)-2-pyrazinyl]-amino]-5- thiazolecarboxamide 3.327 486

′N-(2-Chloro-6-methylphenyl)- 2-[[6-(1H-imidazol-1-yl)-2-pyrazinyl]amino]-5- thiazolecarboxamide 2.68 

Example 487 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[[6-(3-hydroxy-1-pyrrolidinyl)-3-pyridazinyl]amino]-5-thiazolecarboxamide

A

Compound 487A was prepared by an analogous method as that of 473B,except using compound 3-chloro-5-aminopyridazine in place of compound2-bromo-6-aminopyridine.

B

Compound 4878 was prepared by an analogous method as that of 473C,except using compound 487A in place of compound 473B.

C. Title Compound

The title compound was prepared by an analogous method as that of 444B,except using compound 487B in place of compound 444A, and3-hydroxypyrrolidine in place of N-(2-aminoethyl)-morpholine. HPLC Ret.Time 2.493 min.

Example 488 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[[6-(1H-imidazol-1-yl)-3-pyridazinyl]amino]-5-thiazolecarboxamide

Compound 488 was prepared by an analogous method as that of 487C, exceptusing imidazole in place of 3-hydroxypyrrolidine. HPLC Ret. Time 2.61min.

Example 489 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[[3-(methylamino)-2-pyrazinyl]amino]-5-thiazolecarboxamide

A

Compound 489A was prepared by an analogous method as that of 473B,except using compound 2-chloro-3-aminopyrazine in place of compound2-bromo-6-aminopyridine.

B

Compound 489B was prepared by an analogous method as that of 473C,except using compound 489A in place of compound 473B.

C. Title Compound

The title compound was prepared by an analogous method as that of 444B,except using compound 489B in place of compound 444A, and usingmethylamine in place of N-(2-aminoethyl)-morpholine. HPLC Ret. Time 2.81min.

Examples 490 to 494 General Procedure

Compounds 490 to 494 were prepared by an analogous method as that of489C by substituting the appropriate amine.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 490

′N-(2-Chloro-6-methylphenyl)-2- [[3-(3-hydroxy-1-pyrrolidinyl)-2-pyrazinyl]amino]-5- thiazolecarboxamide 2.82  491

′N-(2-Chloro-6-methylphenyl)-2- [[3-(cyclopropylamino)-2-pyrazinyl]amino]-5- thiazolecarboxamide 2.94  492

′N-(2-Chloro-6-methylphenyl)-2- [[3-(4-morpholinyl)-2-pyrazinyl]amino]-5- thiazolecarboxamide 3.643 493

′N-(2-Chloro-6-methylphenyl)-2- [[3-[[2-(4- morpholinyl)ethyl]amino]-2-pyrazinyl]amino]-5- thiazolecarboxamide 2.72  494

′2-[[3-[[2- (Acetylamino)ethyl]amino]-2- pyrazinyl]amino]-N-(2-chloro-6-methylphenyl)-5- thiazolecarboxamide 2.933

Example 495 Preparation of′N-(2-Chloro-6-methylphenyl)-2-(cyclohexylamino)-5-thiazolecarboxamide

Compound 495 was prepared by an analogous method as that of 444B, exceptusing compound 319A in place of compound 444A, and using cyclohexylaminein place of N-(2-aminoethyl)-morpholine. HPLC Ret. Time 3.547 min.

Examples 496 to 500 General Procedure

Compounds 496 to 500 were prepared by an analogous method as that of 495by substituting the appropriate amine.

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 496

′N-(2-Chloro-6-methylphenyl)-2- (methylamino)-5- thiazolecarboxamide2.357 497

′N-(2-Chloro-6-methylphenyl)-2- (cyclopropylamino)-5-thiazolecarboxamide 2.887 498

′N-(2-Chloro-6-methylphenyl)-2- [(phenylmethyl)amino]-5-thiazolecarboxamide 3.500 499

′2-[[2-(Acetylamino)ethyl]amino]- N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide 2.483 500

′N-(2-Chloro-6-methylphenyl)-2- [[(1R)-1-(hydroxymethyl)-3-methylbutyl]amino]-5- thiazolecarboxamide 3.407

Example 501 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[[6-(methoxymethyl)-4-pyrimidinyl]amino]-5-thiazolecarboxamide

A

To the mixture of methyl 4-methoxyacetoacetate (14.6 g, 0.1 moL) andformami-dine hydrogen chloride salt (16.1 g, 0.2 moL) in 70 mL of dryMeOH was added a 25% solution of sodium methoxide (70 mL, 0.3 moL) inMeOH portionwise. A white precipitate was formed immediately. Thereaction mixture was stirred at room temperature for 1.0 hr. Acetic acid(28.6 mL, 0.5 moL) was added and the reaction mixture was concentratedin vacuo. Water was added to the residue and the mixture wassupersaturated with NaCl and extracted with EtOAc (×5). Combinedextracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo togive 8.13 g of compound 501A as a yellow solid.

B

The mixture of compound 501A (5.3 g, 37.8 mmoL) and POCl₃ (40 mL) washeated to reflux for 2.0 hrs. Concentration in vacuo and the residue waspoured into a mixture of ice-CH₂Cl₂. The pH was adjusted to 6.5 to 7using concentrated NH₄OH. The mixture was extracted with CH₂Cl₂ (×3) andcombined extracts were dried over Na₂SO₄. Concentration in vacuofollowed by flash chromatography (CH₂Cl₂-EtOAc: 9:1) on silica gel gave5.33 g of compound 501B as a pale yellow oil.

C

The mixture of compound 5018 (3.2 g, 20 mmoL) and NH₄OH (50 mL) washeated to 85.C in a pressure tube for 3.0 hrs. After cooled to roomtemperature, the reaction mixture was concentrated in vacuo and theresidue was triturated with ether to give 2.81 g of compound 501C as apale yellow solid.

D

Compound 501D was prepared from compound 501C by a method analogous tothat used for the preparation of compound 473B.

E Title Compound

The title compound was prepared from compound 501D by a method analogousto that used for the preparation of compound 473C. HPLC Retentiontime=3.25 min.

Example 502 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[[6-(hydroxymethyl)-4-pyrimidinyl]amino]-5-thiazolecarboxamide

To a solution of compound 501 (56 mg, 0.144 mmoL) in dry CH₂Cl₂ (3.0 mL)cooled at 0.0 was added neat BBr₃ (0.054 mL, 0.574 mmoL). The mixturewas stirred for 1.0 hr at ambient temperature. MeOH was added slowlywith care at 0.0 and the resulting mixture was concentrated in vacuo.Water was added to the residue and pH was adjusted to 7 with Sat′dNaHCO₃. The white precipitate was collected by filtration, rinsed withwater/ether and dried under high vacuum to give 52 mg of Compound 502 asan off-white solid. HPLC Retention time=2.84 min.

Example 503 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[[6-(4-morpholinylmethyl)-4-pyrimidinyl]amino]-5-thiazolecarboxamide

A

To a suspension of compound 502 (44.2 mg, 0.118 mmoL) in 0.5 mL of dryCH₂Cl₂ was added thionyl chloride (0.086 mL, 1.18 mmoL). The reactionmixture was stirred for 5.0 hrs. Concentration in vacuo and the residuewas azeotropic evaporated with CH₂Cl₂ to give 56 mg of 503 as an yellowsolid.

B Title Compound

The mixture of compound 503A (20 mg), morpholine (0.014 mL) anddiisopropylethyl amine (0.09 mL) in 0.5 mL of dry dioxane was heated to85.0 for 4.0 hrs. Concentration in vacuo followed by flashchromatography (CH₂Cl₂-MeOH—NH₄OH: 95:5:0.5) on silica gel gave 15 mg oftitle compound as an off-white solid.

HPLC Retention time=2.52 min.

Examples 504 to 513 General Procedure

Compounds 504 to 513 were prepared from 503A by a route analogous tothat used for the preparation of 503. The compounds of these exampleshave the structure:

HPLC EX. Ret Time NO. Compound Structure Compound Name (min) 504

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[[2- (dimethylamino)ethyl]amino]methyl]-4-pyrimidinyl]amino]-5- thiazolecarboxamide 2.083 505

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[[2-(4-morpholinyl)ethyl]amino]methyl]- 4-pyrimidinyl]amino]-5-thiazolecarboxamide 2.593 506

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[[3-(4-morpholinyl)propyl]amino]methyl]- 4-pyrimidinyl]amino]-5-thiazolecarboxamide 2.163 507

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]methyl]- 4-pyrimidinyl]amino]-5-thiazolecarboxamide 2.693 508

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[(2-1H-imidazol-4-ylethyl)amino]methyl]-4- pyrimidinyl]amino]-5- thiazolecarboxamide 2.143509

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[(3-1H-imidazol-1-ylpropyl)amino]methyl]-4- pyrimidinyl]amino]-5- thiazolecarboxamide1.103 B 510

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[[2-(2-pyridinyl)ethyl]amino]methyl]-4- pyrimidinyl]amino]-5-thiazolecarboxamide 1.113 B 511

′N-(2-Chloro-6-methylphenyl)-2- [[6-[[[2-(3-pyridinyl)ethyl]amino]methyl]-4- pyrimidinyl]amino]-5-thiazolecarboxamide 1.117 B 512

′1-[[6-[[5-[[(2-Chloro-6- methylphenyl)amino]carbonyl]-2-thiazolyl]amino]-4- pyrimidinyl]methyl]-4- piperidinecarboxamide 1.207 B513

2-[[6-[[[2- (Acetylamino)ethyl]amino]methyl]- 4-pyrimidinyl]amino]-N-(2-chloro-6-methylphenyl)-5- thiazolecarboxamide 1.193 B

Example 514 Preparation of′N-(2-Chloro-6-methylphenyl)-2-(2-naphthalenylamino)-5-thiazolecarboxamide

A

Compound 514A was prepared from 473A by an analogous method as that of473B, except using 2-aminonapthaline in place of2-bromo-6-aminopyridine.

B. Title Compound

The title compound was prepared by an analogous method as that of 473C,except using compound 514A in place of compound 473B. HPLC Ret. Time4.11 min.

Example 515 Preparation of′N-(2-Chloro-6-methylphenyl)-2-(2-quinolinylamino)-5-thiazolecarboxamide

A

Compound 515A was prepared from 473A by an analogous method as that of473B, except using 2-aminoquinoline in place of 2-bromo-6-aminopyridine.

B. Title Compound

The title compound was prepared by an analogous method as that of 473C,except using compound 515A in place of compound 473B. HPLC Ret. Time3.94 min.

Example 516 Preparation of′N-(2-Chloro-6-methylphenyl)-2-(3-isoquinolinylamino)-5-thiazolecarboxamide

A

Compound 516A was prepared from 473A by an analogous method as that of473B, except using 3-aminoisoquinoline in place of2-bromo-6-aminopyridine.

B. Title Compound

The title compound was prepared by an analogous method as that of 473C,except using compound 516A in place of compound 473B. HPLC Ret. Time3.94 min.

Example 517 Preparation of′N-(2-Chloro-6-methylphenyl)-2-(2-quinoxalinylamino)-5-thiazolecarboxamide

A

Compound 517A was prepared from 473A by an analogous method as that of473B, except using 2-aminoquinoxaline in place of2-bromo-6-aminopyridine.

B. Title Compound

The title compound was prepared by an analogous method as that of 473C,except using compound 517A in place of compound 473B. HPLC Ret. Time3.927 min.

Example 518 Preparation of′N-(2-Chloro-6-methylphenyl)-4-methyl-2-[[2-methyl-6-(4-morpholinyl)-4-pyrimidinyl]amino]-5-thiazolecarboxamide

A

Compound 518A was prepared from 144 by an analogous method as that of319A.

Compound 518B was prepared by an analogous method as that of 473A,except using 518A in place of 319A.

C

Compound 518C was prepared by an analogous method as that of 473B,except using 518B in place of 473A, and4-amino-6-chloro-2-methylpyrimidine in place of 2-amino-6-bromopyridine.

D

Compound 518D was prepared by an analogous method as that of 473C,except using 518C in place of 473B.

E. Title Compound

The title compound was prepared by an analogous method as that of 444B,except using compound 518D in place of compound 444A, and morpholine inplace of N-(2-aminoethyl)-morpholine. HPLC Ret. Time 3.397 min.

Example 519 Preparation of′N-(2-Chloro-6-methylphenyl)-4-methyl-2-[[2-methyl-6-[[2-(4-morpholinyl)ethyl]amino]-4-pyrimidinyl]amino]-5-thiazolecarboxamide

Compound 519 was prepared by an analogous method as that of 518E, exceptusing N-(2-aminoethyl)-morpholine in place of morpholine. HPLC Ret. Time2.493 min.

Example 520 Alternative Preparation of Compound 321

A

Compound 520A was prepared from 2-aminothiazole according to theprocedure described in UK Patent Application GB 2323595A.

B

To a solution of compound 520A (480 mg, 4.0 mmoL) in dry THF (10 mL)cooled at −78.0 was added a 2.5M solution of n-BuLi (1.68 mL, 4.2 mmoL)in hexane dropwise via a syringe while kept the internal temperaturebelow −75.C. Upon completion of addition, a beige suspension wasobtained. The reaction mixture was stirred for 15 min at −78.C. Asolution of 2-chloro-6-methyl phenyl isocyanate (0.6 mL, 4.4 mmoL) in 5mL of dry THF was added and the reaction mixture was stirred for anadditional 2.0 hrs at −78.C. Saturated aq. NH₄Cl solution (10 mL) wasadded, the mixture was partitioned between EtOAc-water and extractedwith EtOAc (×2). The combined extracts were dried over Na₂SO₄ andconcentration in vacuo to give, after recrystalization fromEtOAc-hexane, 0.99 g of title compound as a pale yellow crystallinematerial.

C

Compound 520C was prepared by a method analogous to that used for thepreparation of compound 473A, using 520B in place of 319A.

D

Compound 520D was prepared from compound 520C by a method analogous tothat used for the preparation of compound 473B.

E. Title Compound

Compound 321 was prepared by a method analogous to that used for thepreparation of compound 473C.

Example 521 Preparation of′2-[(2,6-Dimethyl-4-pyrimidinyl)amino]-N-phenyl-5-thiazolecarboxamide

A

Compound 521A was prepared by an analogous method as that of 520B,except using phenylisocyanate in place of2-chloro-6-methylphenylisocyanate.

B

Compound 521B was prepared by a method analogous to that used for thepreparation of compound 473A, using 521A in place of 319A.

C

Compound 521C was prepared from compound 521B by a method analogous tothat used for the preparation of compound 473B.

D Title Compound

The title compound was prepared by a method analogous to that used forthe preparation of compound 473C. HPLC Ret. Time 1.3 min method B

Example 522 Preparation of′2-[(2,6-Dimethyl-4-pyrimidinyl)methylamino]-N-(2-methylphenyl)-5-thiazolecarboxamide

A

Compound 522A was prepared by an analogous method as that of 520B,except using 2-methylphenylisocyanate in place of2-chloro-6-methylphenyl isocyanate.

B

Compound 522B was prepared by a method analogous to that used for thepreparation of compound 473A, using 522A in place of 319A.

C

Compound 522C was prepared from compound 522B by a method analogous tothat used for the preparation of compound 473B.

D

Sodium hydride (60% in oil; 40 mg; 1 mmol) was added to a solution ofcompound 522C (280 mg; 0.61 mmol) in 2 ml of DMF at room temp. Afterstirring 30 minutes, iodomethane (0.2 ml; 3 mmol) was added and thereaction was stirred 4 hr. After the reaction mixture was partitionedbetween ethyl acetate (50 ml) and water (50 ml), the organic layer waswashed with water (2×50 ml) and brine (50 ml). Drying (MgSO₄) andconcentration afforded an oil that was chromatographed on a 2.5×15 cmsilica gel column using 50-75% ethyl acetate/hexane. The pure fractionswere concentrated and the residue was crystalized from ethylacetate/hexane to afford 100 mg of 522D as a light yellow solid.

E Title Compound

The title compound was prepared by a method analogous to that used forthe preparation of compound 473C. HPLC Ret. Time 1.21 min method B

Example 523 Preparation of′2-[(2,6-Dimethyl-4-pyrimidinyl)amino]-N-(2-methylphenyl)-5-thiazolecarboxamide

Compound 523 was prepared by a method analogous to that used for thepreparation of compound 473C, except using compound 522C in place of473B. HPLC Ret. Time 1.24 min method B

Example 524 Preparation of′N-(3,5-Dimethoxyphenyl)-2-[(2,6-dimethyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide

A

Compound 524A was prepared by an analogous method as that of 520B,except using 3,5-dimethoxyphenylisocyanate in place of2-chloro-6-methylphenyl isocyanate.

B

Compound 524B was prepared by a method analogous to that used for thepreparation of compound 473A, using 524A in place of 319A.

C

Compound 524C was prepared from compound 524B by a method analogous tothat used for the preparation of compound 473B.

D Title Compound

The title compound was prepared by a method analogous to that used forthe preparation of compound 473C, except using compound 524C in place ofcompound 473B HPLC Ret. Time 1.28 min method B

Example 525 Preparation of′N-[2,6-Bis(1-methylethyl)phenyl]-2-[(2,6-dimethyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide

A

Compound 525A was prepared by an analogous method as that of 520B,except using 2,2-diisopropylphenylisocyanate in place of2-chloro-6-methylphenyl isocyanate.

B

Compound 525B was prepared by a method analogous to that used for thepreparation of compound 473A, using 525A in place of 319A.

C

Compound 525C was prepared from compound 525B by a method analogous tothat used for the preparation of compound 473B.

D Title Compound

The title compound was prepared by a method analogous to that used forthe preparation of compound 473C, except using compound 525C in place ofcompound 473B. HPLC Ret. Time 1.6 min method B

Example 526 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[(2,6-dimethyl-4-pyrimidinyl)methylamino]-5-thiazolecarboxamide

A mixture of compound 321 (110 mg; 0.29 mmol), potassium carbonate (138mg; 1 mmol) and iodomethane (0.06 ml; 1 mmol) in DMF was stirred 2 hr atroom temperature. After the reaction mixture was partitioned betweenethyl acetate (25 ml) and water (25 ml), the organic layer was washedwith water (2×25 ml) and brine (25 ml). Drying (MgSO₄) and concentrationafforded an oil that was chromatographed on a 2.5×15 cm silica gelcolumn using 1-4% MeOH/CH₂Cl₂ and the fractions containing compound 526were collected to give 20 mg of product. HPLC Ret. Time 1.3 min methodB.

Example 527 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[(2,6-dimethyl-4-pyrimidinyl)amino]-N-methyl-5-thiazolecarboxamide

Compound 527 was prepared by a method analogous to that used for thepreparation of compound 526, except the fractions containing compound527 were collected to give 60 mg of product. HPLC Ret. Time 1.23 minmethod B

Example 528 Preparation of 2-Bromo-N—,N-(2-chloro-6-methylphenyl)-(4-methoxybenzyl)-5-thiazolecarboxamide

To a cooled (0° C.) THF solution of 2-chloro-6-methyl aniline (2.86 mL,23.3 mmol, 1.10 equiv) was added dropwise a 1.0 M solution of lithiumbis(trimethylsilyl)amide (42.2 mL, 42.2 mmol, 2.00 equiv) via syringe.The homogeneous solution was allowed to stir for 5 minutes, and then aTHF solution of ethyl 2-bromo-5-thiazolecarboxylate (5.00 g, 21.1 mmol,1.00 equiv, prepared in a manner analogous to compound 319A) was addedvia cannula. The solution was allowed to stir for 15 minutes until TLCanalysis showed no remaining starting material. To the reaction was thenadded 4-methoxybenzyl chloride (7.15 mL, 52.7 mmol, 2.5 equiv), followedby a catalytic amount of tetrabutylammonium iodide (1.56 g, 4.22 mmol,0.20 equiv). The homogeneous mixture was allowed to stir overnight atambient temperature and then concentrated in vacuo. The residue waspartitioned between ethyl acetate and water, and the organic extractswere washed with brine and dried over Na₂SO₄. After filtration andremoval of solvent, the product was purified by flash chromatography(10-20% ethyl acetate in hexanes) to afford the title compound as a tansolid (47%).

Example 529 Preparation of N—,N-(2-Chloro-6-methylphenyl)-(4-methoxybenzyl)-2-[(6-bromo-2-pyridinyl)amino]-5-thiazolecarboxamide

Compound 529 was prepared in an analogous manner to 319B, except using528 and 6-bromo-2-aminopyridine as the reactants.

Example 530 Preparation ofN-(2-Chloro-6-methylphenyl)-2-[(6-bromo-2-pyridinyl)amino]-5-thiazolecarboxamide

Compound 529 (0.500 g, 0.919 mmol, 1.00 equiv) was dissolved in 5 mLtrifluoroacetic acid and charged at ambient temperature with 2 mLanisole followed by 1 mL trifluoromethanesulfonic acid. The dark redhomogeneous solution was allowed to stir overnight, and then quenched bycarefully pouring the solution into an ice/sodium bicarbonate mixture. Awhite solid was filtered off and washed sequentially with water, 1:1hexane/ether, and ether to afford the title compound (41%).

Examples 531-538 General Procedure

Compounds 531 to 538 were prepared to the general procedure describedbelow. A 1-dram vial was charged with 530 and excess amine and heated to90° C. overnight. The residue was then purified by reverse phase HPLC toafford the pure compound. For the following examples 531 to 555 “HPLCRet Time” is the HPLC retention time under the following conditions: YMCODS-A C18 S7 3.0×50 mm, 2 min gradient starting from 100% solvent A (10%MeOH, 90% H₂O, 0.1% TFA) to 100% solvent B (90% MeOH, 10% H₂O, 0.1%TFA), flow rate 5 mL/min, λ=220 nM.

HPLC EX. Ret time NO. Compound Structure Compound Name (min) 531

′N-(2-Chloro-6- methylphenyl)-2-[[6-[4- (2-furanylcarbonyl)-1-piperazinyl]-2- pyridinyl]amino]-5- thiazolecarboxamide 1.56 532

′2-[[6-[[3-(1H- Benzimidazol-1- yl)propyl]amino]-2-pyridinyl]amino]-N-(2- chloro-6-methylphenyl)- 5-thiazolecarboxamide1.41 533

′N-(2-Chloro-6- methylphenyl)-2-[[6-[[4- (1H-imidazol-1-yl)butyl]amino]-2- pyridinyl]amino]-5- thiazolecarboxamide 1.24 534

′N-(2-Chloro-6- methylphenyl)-2-[[6-[[5- (1H-imidazol-1-yl)pentyl]amino]-2- pyridinyl]amino]-5- thiazolecarboxamide 1.25 535

′N-(2-Chloro-6- methylphenyl)-2-[[6-[[3- (4-methyl-1-piperazinyl)propyl] amino]-2-pyridinyl] amino]-5- thiazolecarboxamide1.14 536

′N-(2-Chloro-6- methylphenyl)-2-[[6-[[4- (1H-imidazol-1-yl)phenyl]amino]-2- pyridinyl]amino]-5- thiazolecarboxamide 1.29 537

′N-(2-Chloro-6- methylphenyl)-2-[[6-[[6- (1H-imidazol-1-yl)hexyl]amino]-2- pyridinyl]amino]-5- thiazolecarboxamide 1.27 538

′N-(2-Chloro-6- methylphenyl)-2-[[6-[(3- 1H-imidazol-1-ylpropyl)amino]-2- pyridinyl]amino]-5- thiazolecarboxamide 1.24

Example 539 Preparation ofEthyl-2-[(6-bromo-2-pyridinyl)amino]-5-thiazolecarboxylate

Compound 539 was prepared in an analogous manner to 319B, except usingethyl 2-bromo-5-thiazolecarboxylate and 6-bromo-2-aminopyridine as thereactants.

Examples 540-550 General Procedure

Compounds 540 to 550 were prepared according to the general proceduredescribed below. Compound 539 was condensed with the appropriate anilineaccording to the procedure for example 528 to afford the afford thecorresponding N-(4-methoxybenzyl)amide. The intermediate bromopyridinewas then reacted with N-(3-aminopropyl)-imidazole according to theprocedure for examples 531 to 538 to afford the correspondingdiaminopyridine. Removal of the 4-methoxybenzyl group according to theprocedure described for example 530 followed by purification by reversephase preparative HPLC afforded compounds 540 to 550.

HPLC EX. Ret time NO. Compound Structure Compound Name (min) 540

′2-[[6-[[3-(1H-Imidazol- 1-yl)propyl]amino]-2- pyridinyl]amino]-N-(4-methoxyphenyl)-5- thiazolecarboxamide 1.12 541

′2-[[6-[[3-(1H-Imidazol- 1-yl)propyl]amino]-2- pyridinyl]amino]-N-(4-phenoxyphenyl)-5- thiazolecarboxamide 1.48 542

′N-(4-Chlorophenyl)-2- [[6-[[3-(1H-imidazol-1- yl)propyl]amino]-2-pyridinyl]amino]-5- thiazolecarboxamide 1.31 543

′2-[[6-[[3-(1H-Imidazol- 1-yl)propyl]amino]-2- pyridinyl]amino]-N-[1-(phenylmethyl)-1H- indazol-5-yl]-5- thiazolecarboxamide 1.34 544

′N-(2-Ethylphenyl)-2-[[6- [[3-(1H-imidazol-1- yl)propyl]amino]-2-pyridinyl]amino]-5- thiazolecarboxamide 1.18 545

′N-(2,6- Dimethoxyphenyl)-2-[[6- [[3-(1H-imidazol-1- yl)propyl]amino]-2-pyridinyl]amino]-5- thiazolecarboxamide 1.11 546

′N-(2,4- Dimethoxyphenyl)-2-[[6- [[3-(1H-imidazol-1- yl)propyl]amino]-2-pyridinyl]amino]-5- thiazolecarboxamide 1.06 547

′2-[[6-[[3-(1H-Imidazol- 1-yl)propyl]amino]-2- pyridinyl]amino]-N-phenyl-5- thiazolecarboxamide 1.06 548

′2-[[6-[[3-(1H-Imidazol- 1-yl)propyl]amino]-2- pyridinyl]amino]-N-(2-methylphenyl)-5- thiazolecarboxamide 1.11 549

′N-(2-Chlorophenyl)-2- [[6-[[3-(1H-imidazol-1- yl)propyl]amino]-2-pyridinyl]amino]-5- thiazolecarboxamide 1.16 550

′N-(2,6-Diethylphenyl)- 2-[[6-[[3-(1H-imidazol-1- yl)propyl]amino]-2-pyridinyl]amino]-5- thiazolecarboxamide 1.29

Example 551 Preparation ofEthyl-2-[(6-bromo-2-pyridinyl)amino]-4-methyl-5-thiazolecarboxylate

Compound 551 was prepared in an analogous manner to 319B, except usingethyl 2-bromo-4-methyl-5-thiazolecarboxylate and 6-bromo-2-aminopyridineas the reactants.

Examples 552 and 553

Compounds 552 and 553 were prepared using a similar procedure describedfor the preparation of compounds 540 to 550, except using compound 551as the starting material.

HPLC EX. Ret time NO. Compound Structure Compound Name (min) 552

′N-(2-Chloro-6- methylphenyl)-2-[[6-[[3- (1H-imidazol-1-yl)propyl]amino]-2- pyridinyl]amino]-4- methyl-5- thiazolecarboxamide1.19 553

′2-[[6-[[3-(1H-Imidazol- 1-yl)propyl]amino]-2- pyridinyl]amino]-4-methyl-N-[1- (phenylmethyl)-1H- indazol-5-yl]-5- thiazolecarboxamide1.35

Example 554 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[[3-[[3-(1H-imidazol-1-yl)propyl]amino]phenyl]amino]-5-thiazolecarboxamide

A solution of 528 (0.127 g, 0.281 mmol, 1.00 equiv) and3-[N—,N-(tert-butoxycarbonyl)-(3-aminopropyl)-imidazoyl]-1,3-phenylenediamine(0.178 g, 0.563 mmol, 2.00 equiv) in 0.200 mL DMSO was heated at 120° C.in a sealed vial overnight. Purification by reverse phase preparativeHPLC followed by deprotection according to the procedure for compound530 afforded the title compound.

Example 555 Preparation of′N-(2-Chloro-6-methylphenyl)-2-[[5-[[3-(1H-imidazol-1-yl)propyl]amino]-2-nitrophenyl]amino]-5-thiazolecarboxamide

A solution of 2,4-difluoronitrobenzene (0.400 mL, 3.65 mmol, 1.00 equiv)in acetonitrile was charged with K₂CO₃ (0.605 g, 4.38 mmol, 1.20 equiv)followed by ethyl-2-amino-5-thiazolecarboxylate (0.628 g, 3.65 mmol,1.00 equiv) as a solid. The heterogeneous mixture was sealed and heatedto 120° C. overnight. The solution was filtered and then concentrated invacuo. Purification by flash chromatography affordedethyl-2-[(3-fluoro-6-nitro-1-phenyl)amino]-5-thiazolecarboxylate as ayellow solid (9%). This intermediate was coupled with 2-chloro-6-methylaniline according to the procedure for compound 528 to affordN-(2-Chloro-6-methylphenyl)-2-[3-(fluoro-6-nitro-1-phenyl)amino]-5-thiazolecarboxamide(21%). The title compound was synthesized by reacting this intermediatewith excess N-(3-aminopropyl)-imidazole at 80° C. followed bypurification by reverse phase preparative HPLC.

Examples 556-566 General Procedure:

Compounds 556 to 566 were prepared according to the general proceduredescribed below. A mixture of2-bromo-N-[2-chloro-6-methylphenyl]-5-thiazolecarboxamide 319A, ananiline (1 eq), 1.0 N aqueous HCl (0.5 eq) in n-BuOH was heatedovernight at 120° C. in a sealed vial. This was diluted with methanoland the product was isolated by preparative HPLC (YMC S5 ODS 30×100 mmcolumn eluted with a gradient comprised of two solvent mixtures (mixtureA: 10% MeOH, 90% water, and 0.1% TFA; mixture B: 90% MeOH, 10% water,and 0.1% TFA). For anilines substituted with a carboxylic acid group,the reaction mixture was treated with 1 N aqueous NaOH (5 eq) overnightbefore final purification of the product by HPLC. “HPLC Ret Time” is theHPLC retention time under the following conditions: YMC S5 OSD 4.6×30 mm(for 556 to 560) or YMC S7 ODS 3×50 mm column (for 561 to 566), 2 mingradient starting from 100% solvent A (10% MeOH, 90% H₂O, 0.1% TFA) to100% solvent B (90% MeOH, 10% H₂O, 0.1% TFA), flow rate 5 mL/min, λ=220nM.

HPLC EX. Ret time NO. Compound Structure Compound Name (min) 556

N-(2-Chloro-6- methylphenyl)-2- [(3,4,5-trimethoxy- phenyl)amino]-5-thiazolecarboxamide 1.63 557

N-(2-Chloro-6-methyl- phenyl)-2-[(4-methoxy- phenyl)amino]-5-thiazolecarboxamide 1.63 558

N-(2-Chloro-6-methyl- phenyl)-2-[(3-methoxy- phenyl)amino]-5-thiazolecarboxamide 1.70 559

N-(2-Chloro-6-methyl- phenyl)-2-[(2-methoxy- phenyl)amino]-5-thiazolecarboxamide 1.65 560

N-(2-Chloro-6-methyl- phenyl)-2-[(3,5- dimethoxyphenyl)- amino]-5-thiazolecarboxamide 1.55 561

N-(2-Chloro-6-methyl- phenyl)-2-[[4- (dimethylamino)- phenyl]amino]-5-thiazolecarboxamide 1.25 562

N-(2-Chloro-6- methylphenyl)-2-[[4- (4-morpholinyl)phenyl] amino]-5-thiazolecarboxamide 1.24 563

N-(2-Chloro-6- methylphenyl)-2-[[3- (carboxymethyl)- phenyl]amino]-5-thiazolecarboxamide 1.36 564

N-(2-Chloro-6- methylphenyl)-2-[[3- (3-carboxypropyl)- phenyl]amino]-5-thiazolecarboxamide 1.48 565

N-(2-Chloro-6- methylphenyl)-2-[[4- (carboxymethyl) phenyl]amino]-5-thiazolecarboxamide 1.35 566

N-(2-Chloro-6- methylphenyl)-2-[(2- methyl-1H- benzimidazol-5-yl)amino]-5- thiazolecarboxamide 1.27

Example 567N-(2-Chloro-6-methylphenyl)-2-[[1-[3-(1H-imidazol-1-yl)propyl]-1H-benzimidazol-4-yl]amino]-5-thiazolecarboxamide

A mixture of 1-bromo-3-chloropropane (10 mL, 0.10 mmole), imidazole(6.81 gm, 0.10 mmole) in ethanolic NaOEt (41.3 mL, 21 wt %, 1.1 mmole)was heated at reflux for 1 hr. After cooling to RT, this was filteredand the filter cake was washed with EtOH. The solvent was removed fromthe filtrate to afford crude 3-chloro-1-(imidazo-1-yl)-propane as anoil. A portion of the crude chloride (1.07 gm, 7.40 mmole) was added toa mixture of 4-nitro-benzimidazole (1.09 gm, 6.66 mmole) and NaH (293mg, 60% in oil, 8.14 mmole) in DMF (15 mL). After being heated at 60° C.overnight and then 75° C. for 3 hr, the solvent was removed. The residuewas partitioned between water and a mixture of 10% MeOH in DCM. Theorganic phase was separated, dried (Na₂SO₄) and the solvents removed.Radial chromatography (4 mm silica gel plate that was eluted with a stepgradient of DCM containing 2, 3, 4, . . . 10% MeOH) afforded the majorproduct, 1-[3-imidazo-1-ylpropyl]-4-nitro-benzimidazole as a solid (513mg, 28%). A mixture of this material (250 mg) and 10% palladium oncharcoal (200 mg) in EtOH (10 mL) under a hydrogen atmosphere (balloon)was vigorously stirred for 1 hr. Removal of the catalyst by filtrationand the solvent under reduced pressure left the crude4-amino-1-[3-imidazo-1-ylpropyl]-benzimidazole as a solid. A portion ofthis material (46 mg, 0.191 mmole) was added to a mixture of 319A (63mg, 1.0 eq), an aqueous solution of HCl (0.24 mL, 1.0 M, 1.25 eq) andn-BuOH (1 mL). This was heated in a sealed vial at 120° C. for 44 hr.After cooling to RT, 567 (HPLC retention time (YMC ODS S5 4.6×30 mm):1.20 min) was isolated by preparative HPLC.

Example 568N-(2-Chloro-6-methylphenyl)-2-[[1-[2-(1H-imidazol-1-yl)ethyl]-1H-indazol-6-yl]amino]-5-thiazolecarboxamide

A mixture of 1-bromo-2-chloroethane (4.6 mL, 0.055 mole), imidazole(3.40 gm, 0.050 mole) in ethanolic NaOEt (19 mL, 21 wt %, 1 eq) washeated at reflux for 2 hr. After cooling to RT, the reaction wasfiltered and the filter cake was washed with EtOH. The solvent wasremoved from the filtrate to afford crude2-chloro-1-(imidazo-1-yl)-ethane. A portion of the crude chloride (2.24gm, 17.2 mmole) was added to a mixture of 6-nitro-indazole (1.63 gm,10.0 mmole), K₂CO₃ (1.50 mg, 1.1 eq), and KI (1.70 gm, 1.1 eq) in DMF(15 mL). After being heated at 70° C. overnight and then 90° C. for 4hr, the solvent was removed. The residue was partitioned between waterand a mixture of 5% MeOH in DCM. The organic phase was separated, dried(Na₂SO₄) and the solvents removed. Radial chromatography (4 mm silicagel plate that was eluted with a step gradient of DCM containing 0, 1,2% MeOH) afforded 659 mg of 1-[2-imidazo-1-ylethyl]-6-nitro-indazole and450 mg of the isomeric 2-[2-imidazo-1-ylethyl]-6-nitro-indazole. Amixture of 1-[2-imidazo-1-ylethyl]-6-nitro-indazole (650 mg) and 10%palladium on charcoal (600 mg) in EtOH (10 mL) under a hydrogenatmosphere (balloon) was vigorously stirred overnight. Removal of thecatalyst by filtration and the solvent under reduced pressure left thecrude 6-amino-1-[2-imidazo-1-ylethyl]-indazole as a solid. A portion ofthis material (68.1 mg, 1.5 eq) was added to a mixture of 556 (99.3 mg,0.300 mmole), an aqueous solution of HCl (0.45 mL, 1.0 M, 1.5 eq) andn-BuOH (1.5 mL). This was heated in a sealed vial at 120° C. for 44 hr.After cooling to RT, 568 (HPLC retention time (YMC ODS S7 3×50 mm): 1.31min) was isolated by preparative HPLC.

Example 569N-(2-Chloro-6-methylphenyl)-2-[[2-[2-(1H-imidazol-1-yl)ethyl]-2H-indazol-6-yl]amino]-5-thiazolecarboxamide

Beginning with the isomeric 2-[2-imidazo-1-ylethyl]-6-nitro-indazole,569 (HPLC retention time (YMC ODS S7 3×50 mm): 1.28 min) was prepared inthe same manner as 568.

Example 570N-(2-Chloro-6-methylphenyl)-2-[(1-methyl-1H-benzimidazol-6-yl)amino]-5-thiazolecarboxamide

and

Example 571N-(2-Chloro-6-methylphenyl)-2-[(1-methyl-1H-benzimidazol-5-yl)amino]-5-thiazolecarboxamide

Beginning with 5-nitrobenzimidazole and methyl iodide, 570 (HPLCretention time (YMC ODS S7 3×50 mm): 1.23 min) and 571 (HPLC retentiontime (YMC ODS S7 3×50 mm): 1.23 min) were prepared in the same manner ascompounds 557 and 558.

Example 572N-(2-Chloro-6-methylphenyl)-2-[[2-[3-(1H-imidazol-1-yl)propyl]amino]-1H-benzimidazol-5-yl]amino]-5-thiazolecarboxamide

A mixture of 2-chloro-5-nitro-benzimidazole (985 mg, 5.0 mmole) and1-(3-aminopropyl)-imidazole (1.8 mL, 3 eq) in toluene (15 mL) was heatedat reflux for 5 hr. The reaction was partitioned between EtOAc and brineto give a precipitate that was collected by filtration. Flashchromatography of this material (silica gel; stepwise gradient elutionwith mixtures of DCM containing 1, 2, 3, . . . 10% MeOH) afforded2-[3-[imidazo-1-yl]-propylamino]-5-nitro-benzimidazole (550 mg) as asolid. This material was combined with 10% Pd on charcoal (500 mg),suspended in EtOH, and stirred under a hydrogen atmosphere (balloon)overnight. Removal of the catalyst by filtration and the solvent underreduced pressure left the crude5-amino-2-[3-imidazo-1-ylpropylamino]-benzimidazole as a solid. Aportion of this material (77 mg, 0.30 mmole) was added to a mixture of319A (99 mg, 1.0 eq), an aqueous solution of HCl (0.60 mL, 1.0 M, 2 eq)and n-BuOH (1.5 mL). This was heated in a sealed vial at 120° C. for 20hr. After cooling to RT, 572 (HPLC retention time (YMC ODS S7 3×50 mm):1.20 min) was isolated by preparative HPLC.

Example 573N-(2-Chloro-6-methylphenyl)-2-[[2-(4-morpholinylmethyl)-1H-benzimidazol-5-yl]amino]-5-thiazolecarboxamide

A mixture of 3,4-diamino-nitrobenzene (15.3 g, 0.10 mole) andchloroacetic acid (14.18 gm, 1.5 eq) in 5.0 N aqueous HCl (80 mL) washeated at reflux for 1 hr. After cooling to RT, the reaction wasfiltered through celite and the filtrate was stored at 0° C. for 2 days.The crystals that formed, were collected and recrystallized from amixture of EtOH and water to give 7.2 gm of the hydrogen chloride saltof 2-chloromethyl-5-nitro-benzimidazole. A portion of this salt (528 mg,2.13 mmole) and morpholine (1.31 mL, 7 eq) in toluene (15 mL) wereheated at reflux for 4 hr. After cooling to RT, the reaction wasfiltered and the filter cake was washed with toluene. The solvent wasremoved from the filtrate to leave the crude2-[N-morpholinylmethyl]-5-nitro-benzimidazole as an oil. A portion ofthis material (657 mg) and 10% palladium on charcoal (650 mg) in EtOH(10 mL) was stirred overnight under a hydrogen atmosphere (balloon).Removal of the catalyst by filtration and the solvent left the crude5-amino-2-[N-morpholinylmethyl]-benzimidazole as an oil. A portion ofthis material was coupled with 556 as described for 570 to afford 573(HPLC retention time (YMC ODS S7 3×50 mm): 0.92 min).

Example 574N-(2-Chloro-6-methylphenyl)-2-[[2-(1H-imidazol-1-ylmethyl)-1H-benzimidazol-5-yl]amino]-5-thiazolecarboxamide

Beginning with imidazole and 2-chloromethyl-5-nitro-benzimidazolecompound 574 (HPLC retention time (YMC ODS S7 3×50 mm): 1.17 min) wasprepared in the same manner as compounds 570.

Example 575N-(2-Chloro-6-methylphenyl)-2-[[3-[[5-(1H-imidazol-1-yl)-2-pyridinyl]amino]phenyl]amino]-5-thiazolecarboxamide

A mixture of 3-nitroaniline (2.91 gm, 21.1 mmole) and2,5-dibromopyridine (5.0 gm, 1 eq) was heated at 185° C. for 1 hr. Aftercooling to RT, the solid was broken up and treated with a mixture ofsaturated aq. NaHCO₃ and 10% MeOH in DCM. The suspended solid wascollected by filtration and washed with a little 10% MeOH in DCM andthen water to leave, after drying, 3.72 gm of crudeN-[5-bromo-pyridin-2-yl]-5-nitroaniline. A portion of this material (500mg, 1.70 mmole) was combined with imidazole (116 mg, 1 eq), CuI (81 mg,0.25 eq), and K₂CO₃ (235 mg, 1 eq) in DMF (2 mL) and the mixture washeated at 130° C. for 2 days. After cooling to RT, the solvent wasremoved and the residue was partitioned between water and a mixture of20% MeOH in DCM. The organic phase was removed, dried (Na₂SO₄), and thesolvents removed to leave the crudeN-[5-imidazo-1-yl]-pyridin-2-yl]-5-nitroaniline as a solid. This wastaken and treated with 10% palladium on charcoal (650 mg) in EtOH undera hydrogen atmosphere for 1.5 hr. Removal of the catalyst and then thesolvent left the crude N-[5-imidazo-1-yl]-pyridin-2-yl]-5-aminoaniline.It was purified by radial chromatography (4 mm silica gel plate that waseluted with a step gradient of DCM containing 1, 2, 3, . . . 6% MeOH).The aniline was then coupled with 319A as described for 570 to afford575 (HPLC retention time (YMC ODS S5 4.6×30 mm): 1.42 min).

Example 576N-(2-Chloro-6-methylphenyl)-2-[[3-[3-(1H-imidazol-1-yl)propoxy]phenyl]amino]-5-thiazolecarboxamide

and

Example 577N-(2-Chloro-6-methylphenyl)-2-[[4-[3-(1H-imidazol-1-yl)propoxy]phenyl]amino]-5-thiazolecarboxamide

A suspension of 3-nitrophenol (837 mg, 6.02 mmole),1-chloro-3-[imidazo-1-yl]-propane (871 mg, 1 eq), K₂CO₃ (3.3 gm, 4 eq)and NaI (1.0 gm, 1.1 eq) in DMF was heated at 120° C. for 6 hr. Aftercooling to RT, the reaction was filtered and the filter cake was washedwith DMF. The solvent was removed from the filtrate and the residue waschromatographed (radial chromatography; 4 mm silica gel plate that waseluted with a step gradient of DCM containing 0, 1, 2.5, 5, 7.5% MeOH)to afford 400 mg of 3-[3-imidazo-1-ylpropyloxy]]-nitrobenzene. This wastreated with 10% palladium on charcoal (400 mg) in EtOH under a hydrogenatmosphere for 4 hr. Removal of the catalyst and the solvent left3-[3-imidazo-1-ylpropyloxy]]-aniline was then coupled with 319A asdescribed for 570 to afford 576 (HPLC retention time (YMC ODS S5 4.6×30mm): 1.33 min). Beginning with 4-nitrophenol and1-chloro-3-[imidazo-1-yl]-propane 577 (HPLC retention time (YMC ODS S54.6×30 mm): 1.42 min) was prepared in a similar manner as 576.

Example 578N-(2-Chloro-6-methylphenyl)-2-[[4-[2-(1H-imidazol-1-yl)ethoxy]-3-methoxyphenyl]amino]-5-thiazolecarboxamide

Beginning with 2-methoxy-4-nitrophenol and1-chloro-3-[imidazo-1-yl]-ethane, 578 (HPLC retention time (YMC ODS S54.6×30 mm): 1.35 min) was prepared in a similar manner as 576.

Example 579N-(2-Chloro-6-methylphenyl)-2-[[3-[[[3-(1H-imidazol-1-yl)propyl]amino]sulfonyl]phenyl]amino]-5-thiazolecarboxamide

and

Example 580N-(2-Chloro-6-methylphenyl)-2-[[4-[[[3-(1H-imidazol-1-yl)propyl]amino]sulfonyl]phenyl]amino]-5-thiazolecarboxamide

3-Imidazo-1-yl-propylamine (2.04 mL, 2.5 eq) was added to a solution of3-nitro-benzenesulfonyl chloride (1.5 gm, 6.77 mmole) in THF (20 mL) atRT. After 1 hr, the solvent was removed and the residue was partitionedbetween water and a mixture of 10% MeOH in DCM. The organic phase wasseparated, washed with water and dried (Na2SO4). The crudeN-[3-[imidazo-1-yl]-propyl]-3-nitro-benzenesulfonamide was treated with10% palladium on charcoal (2 gm) in THF (60 mL) under a hydrogenatmosphere overnight. Removal of the catalyst and then the solvent leftcrude 3-amino-N-[3-[imidazo-1-yl]-propyl]-benzenesulfonamide which wasthen coupled with 319A as described for 570 to afford 579 (HPLCretention time (YMC ODS S7 3×50 mm): 1.22 min). Beginning with4-nitro-benzenesulfonyl chloride and 3-[imidazo-1-yl]-propylamine, 580(HPLC retention time (YMC ODS S7 3×50 mm): 1.21 min) was prepared in asimilar manner as 579.

What is claimed is:
 1. A cyclic compound of the following formula I or asalt thereof:

where Q is thiazole optionally substituted with R₁; Z is a single bond;X₁ and X₂ together form ═O; R₁ is is hydrogen or alkyl; R₆ is alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, eachof which is unsubstituted or substituted with Z₁, Z₂ and one or moregroups Z₃; q is 1 or 2; R₂ is hydrogen or alkyl; R₃ is —C(O)—NR₇R₈,wherein R⁷ is aryl, which is unsubstituted or substituted with Z₁, Z₂and one or more groups Z₃; R₄ is hydrogen or alkyl; R₅ is aryl which isunsubstituted or substituted with Z₁, Z₂ and one or more groups Z₃; R₈,R₉, R₁₀, R₁₁ and R₁₂: (1) are each independently hydrogen or R₆; or (2)any two of R₉, R₁₀ and R₁₁ may together be alkylene or alkenylenecompleting a 3- to 8-membered saturated or unsaturated ring togetherwith the nitrogen atoms to which they are attached, which ring isunsubstituted or substituted with Z₁, Z₂ and Z₃; R₁₃ is: (1) cyano; (2)nitro; (3) —NH₂; (4) —NHOalkyl; (5) —OH; (6) —NHOaryl; (7) —NHCOOalkyl;(8) —NHCOOaryl; (9) —NHSO₂alkyl; (10) —NHSO₂aryl; (11) aryl; (12)heteroaryl; (13) —Oalkyl; or (14) —Oaryl; R₁₄ is: (1) —NO₂; (2)—COOalkyl; or (3) —COOaryl; Z₁, Z₂ and Z₃ are each independently: (1)hydrogen or Z₆, where Z₆ is (i) alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl,alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) agroup (i) which is itself substituted by one or more of the same ordifferent groups (i); or (iii) a group (i) or (ii) which is substitutedby one or more of the following groups (2) to (16) of the definition ofZ₁, Z₂ and Z₃; (2) —OH or —OZ₆; (3) —SH or —SZ₆; (4) —C(O)_(q)H,—C(O)_(q)Z₆, or —O—C(O)_(q)Z₆; (5) —SO₃H, —S(O)_(q)Z₆; orS(O)_(q)N(Z₉)Z₆; (6) halo; (7) cyano; (8) nitro; (9) —Z₄—NZ₇Z₈; (10)—Z₄—N(Z₉)—Z₅—NZ₇Z₈; (11) —Z₄—N(Z₁₀)—Z₅—Z₆; (12) —Z₄—N(Z₁₀)—Z₅—H; (13)oxo; (14) —O—C(O)—Z₆; (15) any two of Z₁, Z₂, and Z₃ may together bealkylene or alkenylene completing a 3- to 8-membered saturated orunsaturated ring together with the atoms to which they are attached; or(16) any two of Z₁, Z₂, and Z₃ may together be —O—(CH₂)_(r)—O—, where ris 1 to 5, completing a 4- to 8-membered ring together with the atoms towhich they are attached; Z₄ and Z₅ are each independently: (1) a singlebond; (2) —Z₁₁—S(O)_(q)—Z₁₂—; (3) —Z₁₁—C(O)—Z₁₂—; (4) —Z₁₁—C(S)—Z₁₂—;(5) —Z₁₁—O—Z₁₂—; (6) —Z₁₁—S—Z₁₂—; (7) —Z₁₁—O—C(O)—Z₁₂—; or (8)—Z₁₁—C(O)—O—Z₁₂—; Z₇, Z₈, Z₉ and Z₁₀: (1) are each independentlyhydrogen or Z₆; (2) Z₇ and Z₈, or Z₆ and Z₁₀, may together be alkyleneor alkenylene, completing a 3- to 8-membered saturated or unsaturatedring together with the atoms to which they are attached, which ring isunsubstituted or substituted with Z₁, Z₂ and Z₃; or (3) Z₇ or Z₈,together with Z₉, may be alkylene or alkenylene completing a 3- to8-membered saturated or unsaturated ring together with the nitrogenatoms to which they are attached, which ring is unsubstituted orsubstituted with Z₁, Z₂ and Z₃; Z₁₁ and Z₁₂ are each independently: (1)a single bond; (2) alkylene; (3) alkenylene; or (4) alkynylene; and Z₁₃is: (1) a single bond; (2) —Z₁₁—S(O)_(q)—Z₁₂—; (3) —Z₁₁—C(O)—Z₁₂—; (4)—Z₁₁—C(S)—Z₁₂—; (5) —Z₁₁—O—Z₁₂—; (6) —Z₁₁—S—Z₁₂—; (7) —Z₁₁—O—C(O)—Z₁₂—;(8) —Z₁₁—C(O)—O—Z₁₂—; (9) —C(NR₁₃)—; (10) —C(CHR₁₄)—; or (11)—C(C(R₁₄)₂)—.
 2. A compound of claim 1, wherein R₁ is hydrogen.
 3. Acompound of claim 1, wherein R₂ is hydrogen.
 4. A compound of claim 1,wherein R₄ is hydrogen.
 5. A compound of formula II or salt thereof:

where n is 1; X₃ is oxygen; A is nitrogen; B is sulfur R₁ is hydrogen oralkyl; R₆ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, orheterocycloalkyl, each of which is unsubstituted or substituted with Z₁,Z₂ and one or more (preferably, one or two) groups Z₃; q is 1 or 2; R₂is hydrogen or alkyl; R₃ is —C(O)—NR₇R₈, wherein R⁷ is aryl, which isunsubstituted or substituted with Z₁, Z₂ and one or more groups Z₃; R₄is hydrogen or alkyl; R₅ is aryl which is unsubstituted or substitutedwith Z₁, Z₂ and one or more groups Z₃; R₈, R₉, R₁₀, R₁₁ and R₁₂: (1) areeach independently hydrogen or R₆; or (2) any two of R₉, R₁₀ and R₁₁ maytogether be alkylene or alkenylene completing a 3- to 8-memberedsaturated or unsaturated ring together with the nitrogen atoms to whichthey are attached, which ring is unsubstituted or substituted with Z₁,Z₂ and Z₃; R₁₃ is: (1) cyano; (2) nitro; (3) —NH₂; (4) —NHOalkyl; (5)—OH; (6) —NHOaryl; (7) —NHCOOalkyl; (8) —NHCOOaryl; (9) —NHSO₂alkyl;(10) —NHSO₂aryl; (11) aryl; (12) heteroaryl; (13) —Oalkyl; or (14)—Oaryl; R₁₄ is: (1) —NO₂; (2) —COOalkyl; or (3) —COOaryl; Z₁, Z₂ and Z₃are each independently: (1) hydrogen or Z₆, where Z₆ is (i) alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl,heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itselfsubstituted by one or more of the same or different groups (i); or (iii)a group (i) or (ii) which is substituted by one or more of the followinggroups (2) to (16) of the definition of Z₁, Z₂ and Z₃; (2) —OH or —OZ₆;(3) —SH or —SZ₆; (4) —C(O)_(q)H, —C(O)_(q)Z₆, or —O—C(O)_(q)Z₆; (5)—SO₃H, —S(O)_(q)Z₆; or S(O)_(q)N(Z₉)Z₆; (6) halo; (7) cyano; (8) nitro;(9) —Z₄—NZ₇Z₈; (10) —Z₄—N(Z₉)—Z₅—NZ₇Z₈; (11) —Z₄—N(Z₁₀)—Z₅—Z₆; (12)—Z₄—N(Z₁₀)—Z₅—H; (13) oxo; (14) —O—C(O)—Z₆; (15) any two of Z₁, Z₂, andZ₃ may together be alkylene or alkenylene completing a 3- to 8-memberedsaturated or unsaturated ring together with the atoms to which they areattached; or (16) any two of Z₁, Z₂, and Z₃ may together be—O—(CH₂)_(r)—O—, where r is 1 to 5, completing a 4- to 8-membered ringtogether with the atoms to which they are attached; Z₄ and Z₅ are eachindependently: (1) a single bond; (2) —Z₁₁—S(O)_(q)—Z₁₂—; (3)—Z₁₁—C(O)—Z₁₂—; (4) —Z₁₁—C(S)—Z₁₂—; (5) —Z₁₁—O—Z₁₂—; (6) —Z₁₁—S—Z₁₂—;(7) —Z₁₁—O—C(O)—Z₁₂—; or (8) —Z₁₁—C(O)—O—Z₁₂—; Z₇, Z₈, Z₉ and Z₁₀: (1)are each independently hydrogen or Z₆; (2) Z₇ and Z₈, or Z₆ and Z₁₀, maytogether be alkylene or alkenylene, completing a 3- to 8-memberedsaturated or unsaturated ring together with the atoms to which they areattached, which ring is unsubstituted or substituted with Z₁, Z₂ and Z₃;or (3) Z₇ or Z₈, together with Z₉, may be alkylene or alkenylenecompleting a 3- to 8-membered saturated or unsaturated ring togetherwith the nitrogen atoms to which they are attached, which ring isunsubstituted or substituted with Z₁, Z₂ and Z₃; Z₁₁ and Z₁₂ are eachindependently: (1) a single bond; (2) alkylene; (3) alkenylene; or (4)alkynylene; and Z₁₃ is: (1) a single bond; (2) —Z₁₁—S(O)_(q)—Z₁₂—; (3)—Z₁₁—C(O)—Z₁₂—; (4) —Z₁₁—C(S)—Z₁₂—; (5) —Z₁₁—O—Z₁₂—; (6) —Z₁₁—S—Z₁₂—;(7) —Z₁₁—O—C(O)—Z₁₂—; (8) —Z₁₁—C(O)—O—Z₁₂—; (9) —C(NR₁₃)—; (10)—C(CHR₁₄)—; or (11) —C(C(R₁₄)₂)—.
 6. A compound of claim 9, wherein R₅is aryl which is unsubstituted or independently substituted with one ormore alkyl or halo.
 7. A pharmaceutical composition, comprising apharmaceutically acceptable vehicle ordiluent and at least one compoundof claim
 1. 8. A pharmaceutical composition, comprising apharmaceutically acceptable vehicle ordiluent and at least one compoundof claim 8.